Inhibitors of HCV NS5B polymerase

ABSTRACT

The present invention relates to compounds, process for their synthesis, compositions and methods for the treatment and prevention of hepatitis C virus (HCV) infection. In particular, the present invention provides novel compounds, pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment or prevention of HCV infection. The present invention also provides processes and intermediates for the synthesis of these compounds.

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application No. 60/518,542, filed Nov. 7, 2003, and which ishereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to compounds, process for their synthesis,compositions and methods for the treatment and prevention of hepatitis Cvirus (HCV) infection. In particular, the present invention providesnovel compounds, pharmaceutical compositions containing such compoundsand methods for using these compounds in the treatment or prevention ofHCV infection. The present invention also provides processes andintermediates for the synthesis of these compounds.

BACKGROUND

Hepatitis C virus (HCV) is the major etiological agent ofpost-transfusion and community-acquired non-A non-B hepatitis worldwide.It is estimated that over 150 million people worldwide are infected bythe virus. A high percentage of carriers become chronically infected andmany progress to chronic liver disease, so-called chronic hepatitis C.This group is in turn at high risk for serious liver disease such asliver cirrhosis, hepatocellular carcinoma and terminal liver diseaseleading to death.

The mechanism by which HCV establishes viral persistence and causes ahigh rate of chronic liver disease has not been thoroughly elucidated.It is not known how HCV interacts with and evades the host immunesystem. In addition, the roles of cellular and humoral immune responsesin protection against HCV infection and disease have yet to beestablished. Immunoglobulins have been reported for prophylaxis oftransfusion-associated viral hepatitis, however, the Center for DiseaseControl does not presently recommend immunoglobulins treatment for thispurpose. The lack of an effective protective immune response ishampering the development of a vaccine or adequate post-exposureprophylaxis measures, so in the near-term, hopes are firmly pinned onantiviral interventions.

Various clinical studies have been conducted with the goal ofidentifying pharmaceutical agents capable of effectively treating HCVinfection in patients afflicted with chronic hepatitis C. These studieshave involved the use of interferon-alpha, alone and in combination withother antiviral agents. Such studies have shown that a substantialnumber of the participants do not respond to these therapies, and ofthose that do respond favorably, a large proportion were found torelapse after termination of treatment.

Until recently, interferon (IFN) was the only available therapy ofproven benefit approved in the clinic for patients with chronichepatitis C. However the sustained response rate is low, and interferontreatment also induces severe side-effects (i.e. retinopathy,thyroiditis, acute pancreatitis, depression) that diminish the qualityof life of treated patients. Recently, interferon in combination withribavirin has been approved for patients non-responsive to IFN alone.However, the side effects caused by IFN are not alleviated with thiscombination therapy.

Therefore, a need exists for the development of effective antiviralagents for treatment of HCV infection that overcomes the limitations ofexisting pharmaceutical therapies.

General Viral polymerases are attractive targets for antiviral drugdevelopment. For example, inhibitors of Viral RNA polymerase activityhave been described; see, for example, JAEN, Juan, et. al., WO 0177091,Altamura et. al., WO 00/06529 and Bailey et. al., WO 00/10573, whichreferences are incorporated by reference herein.

The HCV protein NS5B is an RNA dependent RNA polymerase, see, e.g.,Lohmann et al. (1997) J. Virol. 71:8416–8428, Behrens et al. (1996) EMBOJ. 15:12–22 and Ishido et al. (1998) Biochem. Biophys. Res. Comm.244:35–40, which references are incorporated by reference herein. Thesequence of various genotypes of HCV NS5B are known (Kato et al. (1990)Proc. Natl. Acad. Sci. USA. 87:9524–9528; Webster, G., et al. (2000)Balliere's Clinical Gastroenterology 14, 229–240; van Doom, L. J. (1994)J. of Medical Virology 43, 345–356; Houghton, M. (1996) Hepatitis Cviruses Fields Virology: Third Edition, edited by B. N. Fields, D. M.Knipe, P. M. Howley, et al. Lippincott-Raven Publishers, Philadelphia,pp. 1035–1058; Lau, J. Y. et. al., J Infect Dis. 1995, 171(2), 281–9).However, NS5B contains sequence motifs that are highly conserved amongall the RNA-dependent RNA polymerases characterized to date.

SUMMARY

The present invention provides compounds, compositions and methods thatare useful for treating viral infections and associated diseases,particularly HCV infections and associated diseases. The compounds ofthe invention inhibit viral replication, preferably HCV replication. Themethods of the invention comprise administering to an infected orsusceptible host a therapeutically or prophylactically effective amountof a compound as represented by Formula I,

Formula I

wherein:

-   X₁, X₂, X₃ and X₄ are independently N or C—R₁ provided that only one    of X₁, X₂, X₃ and X₄ is N;

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, halogen, —CN,C₁₋₆-alkoxy, C₁₋₆-fluoroalkyl, C₁₋₆-fluroalkoxy and C₁₋₆-alkylthio;

any two adjacent —CR₁ may be taken together to form a fused aromatic orheteroaromatic substituent of two to three rings;

A is selected from the group consisting of —OSO₂-M, —NR₂SO₂-M, —OCR₂,R′₂-M and —CR₂, R′₂ SO_(n)-M;

B is selected from the group —CR₂═N—NH—CO-Z, —CR₂═CR′₂NHCO-Z,—NHCR₂═CR′₂CO-Z and -1,2-cyclopropyl-NHCO-Z;

Z is selected from the group -M′, —(CR₂R′₂)_(m)-M′, —O-M′, —NR₂-M′, and—(CR₂R′₂)_(m)—O-M′;

R₂ and R₁₂ are independently selected from the group consiting of H andC₁₋₆ alkyl;

M and M′ are independently selected from aryl optionally substitutedwith 1 to 3 R₁, heteroaryl optionally substituted with 1 to 3 R₁ andcycloalkyl of 3 to 8 carbons;

n=0, 1, or 2;

m=1, 2, 3 or 4;

or a pharmaceutically acceptable salt or prodrug thereof.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

The abbreviations used herein are conventional, unless otherwisedefined.

The terms “treat”, “treating” and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

The terms “prevent”, “preventing” and “prevention” refer to a method of‘barring a subject from acquiring a disease. As used herein, “prevent”,“preventing” and “prevention” also include reducing a subject's risk ofacquiring a disease.

The term “therapeutically effective amount” refers to that amount of thecompound being administered sufficient to prevent development of oralleviate to some extent one or more of the symptoms of the diseasebeing treated.

The term “viral infection” refers to the introduction of a virus intocells or tissues, e.g., hepatitis C virus (HCV). In general, theintroduction of a virus is also associated with replication. Viralinfection may be determined by measuring virus antibody titer in samplesof a biological fluid, such as blood, using, e.g., enzyme immunoassay.Other suitable diagnostic methods include molecular based techniques,such as RT-PCR, direct hybrid capture assay, nucleic acid sequence basedamplification, and the like. A virus may infect an organ, e.g., liver,and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease andhepatocellular carcinoma.

“Flaviviridae virus”, as used herein, refers to a virus of the familyFlaviviridae, which family includes the Flavivirus, Pestivirus andHepacivirus or hepatitis C-like virus genera. Representative species ofthe genus Flavivirus include yellow fever virus, tick-borne encephalitisvirus, Rio Bravo virus, Japanese encephalitis virus, Tyuleniy virus,Ntaya virus, Uganda S virus, Dengue virus and Modoc virus.Representative species of the genus Pestivirus include bovine diarrheavirus, border disease virus and hog cholera virus. A representativespecies of the genus of hepatitis C-like viruses is hepatitis C virus.Unassigned viruses in the family Flaviviridae are included in themeaning of Flaviviridae virus.

The term “modulate” refers to the ability of a compound to increase ordecrease the catalytic activity of a viral polymerase, e.g. a viral RNApolymerase. A modulator preferably activates the catalytic activity of aviral polymerase or more preferably activates or inhibits the catalyticactivity of a viral polymerase depending on the concentration of thecompound exposed to the viral polymerase or most preferably inhibits thecatalytic activity of a viral polymerase.

The term “modify” refers to the act of altering, in whole or in part,the structure of a molecule, e.g., a protein. Modification may becovalent or noncovalent, and includes, but is not limited to,aggregation, association, substitution, conjugation and/or eliminationof a chemical group. Modification may alter the function or otherproperties (e.g., chemical, physical) of the molecule.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁–C₈ means1–8 eight carbons). Examples of saturated hydrocarbon radicals includegroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)ethyl, cyclopropylmethyl,homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl,n-octyl, and the like. An unsaturated alkyl group is one having one ormore double bonds or triple bonds. Examples of unsaturated alkyl groupsinclude vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, I- and 3-propynyl,3-butynyl, and the higher homologs and isomers. A “lower alkyl” is ashorter chain alkyl having eight or fewer carbon atoms.

The terms “alkoxy . . . alkylcylamino” and “alkylthio” refer to thosegroups having an alkyl group attached to the remainder of the moleculethrough an oxygen, nitrogen or sulfur atom, respectively. Similarly, theterm “dialkylamino” is used in a conventional sense to refer to —NRR′wherein the R groups can be the same or different alkyl groups.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, fully saturated orcontaining from 1 to 3 degrees of unsaturation, consisting of the statednumber of carbon atoms and from one to three heteroatoms selected fromthe group consisting of O, N, and S, and wherein the nitrogen and sulfuratoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) O, N and S may be placed atany interior position of the heteroalkyl group. Examples include—CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may beconsecutive, such as, for example, —CH₂—NH—OCH₃. Also included in theterm “heteroalkyl” are those radicals described in more detail below as“heterocycloalkyl”.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “Fluoroalkyl,” aremeant to include monofluoroalkyl and polyfluoroalkyl.

The term “aryl,” employed alone or in combination with other terms(e.g., aryloxy, arylthioxy, aralkyl) means, unless otherwise stated, anaromatic substituent which can be a single ring or multiple rings (up tothree rings) which are fused together or linked covalently. The term“heteroaryl” is meant to include those aryl rings which contain fromzero to four heteroatoms selected from N, O, and S, wherein the nitrogenand sulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. The “heteroaryl” groups can be attached to theremainder of the molecule through a heteroatom. Non-limiting examples ofaryl and heteroaryl groups include phenyl, 1-naphthyl, 2-napthyl,4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 -pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 1-indolyl,5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl.

Substituents for each of the above noted aryl ring systems are selectedfrom the group of acceptable substituents described below. The term“aralkyl” is meant to include those radicals in which an aryl orheteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl,pyridylmethyl and the like) or a heteroalkyl group (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl . . . heteroalkyl” and “aryl”) aremeant to include both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″—SR′, -halogen, —SiR′R″R, —OC(O)R′, —C(O)R′, —CO₂R′,CONR′R″, —OC(O)NR′R″—NR′C(O)R′, —NR′—C(O)NR″R′″, —NR′COOR″,—NH—C(NH₂)═NH, —NR′C(NH₂)═N—H, —NH—C(NH₂)═NR′, —S(O)R′, S(O)₂R′,—S(O)₂NR′R″, —CN and —NO₂ in a number ranging from zero to (2N+1), whereN is the total number of carbon atoms in such radical. R′, R″ and X″each independently refer to hydrogen, unsubstituted Cl—COalkyl andheteroalkyl, unsubstituted aryl, aryl substituted with 1–3 halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C1–C4)alkylgroups. When R′ and R″ are attached to the same nitrogen atom, they canbe combined with the nitrogen atom to form a 3–7 membered ring. Forexample, —NR′R″ is meant to include 1-pyrrolidinyl and 4-morpholinyl.From the above discussion of substituents, one of skill in the art willunderstand that the term “alkyl” is meant to include groups such ashaloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃,—C(O)CH₂OCH₃, and the like).

Similarly, substituents for the aryl groups are varied and are selectedfrom: halogen, —OR, —OC(O)R, —NR′R″, —SR, —R′, —CN, —NO₂, —CO₂R′,—CONR′R:′, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂, perfluoro(CI–C4)alkoxy, andperfluoro(CI–C4)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R′, R″ and R′″are independently selected from hydrogen, (C1–C8)alkyl and heteroalkyl,unsubstituted aryl, (unsubstituted aryl)-(C1–C4)alkyl, and(unsubstituted aryloxy-(C₁–C₄)alkyl.

Two of the substituents on adjacent atoms of the aryl ring mayoptionally be replaced with a substituent of the formula—S—C(O)—(CH₂)_(q)—R—, wherein S and R are independently —NH—, —O—, —CH₂—or a single bond, and the subscript q is an integer of from 0 to 2.Alternatively, two of the substituents on adjacent atoms of the arylring may optionally be replaced with a substituent of the formula-A-(CH₂)_(w)-B-, wherein A and B are independently —CH₂—, —O—, —NH—,—S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and w is an integerof from 1 to 3. One of the single bonds of the new ring so formed mayoptionally be replaced with a double bond. Alternatively, two of thesubstituents on adjacent atoms of the aryl ring may optionally bereplaced with a substituent of the formula —(CH₂)_(w)-G-(CH₂)_(w), wherew and w′ are independently integers of from 0 to 3, and G is —O—, —NR′—,—S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. The substituent R′ in —NR′— and—S(O)₂NR′— is selected from hydrogen or unsubstituted (CI–C6)alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), and sulfur (S).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic,citric, tartaric, methanesulfonic, and the like. Also included are saltsof amino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactouronic acids and the like (see, for example,Berge, S. M., et. al. (1977) J. Pharm. Sci., 66:1–19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner.

The parent form of the compound differs from the various salt forms incertain physical properties, such as solubility in polar solvents, butotherwise the salts are equivalent to the parent form of the compoundfor the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex-vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent. Prodrugs are oftenuseful because, in some situations, they may be easier to administerthan the parent drug. They may, for instance, be bioavailable by oraladministration whereas the parent drug is not. The prodrug may also haveimproved solubility in pharmacological compositions over the parentdrug. A wide variety of prodrug derivatives are known in the art, suchas those that rely on hydrolytic cleavage or oxidative activation of theprodrug. An example, without limitation, of a prodrug would be acompound of the present invention which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound of the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are all intended to beencompassed within the scope of the present invention unless otherwisestated.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

Description of the Embodiments

General Viral polymerases are attractive targets for antiviral drugdevelopment. For example, inhibitors of Viral RNA polymerase activityhave been described; see, for example, JAEN, Juan, et. al., WO 0177091,Altamura et. al., WO 00/06529 and Bailey et. al., WO 00/10573, whichreferences are incorporated by reference herein.

The HCV protein NS5B is an RNA dependent RNA polymerase, see, e.g.,Lohmann et al. (1997) J. Virol. 71:8416–8428, Behrens et al. (1996) EMBOJ. 15:12–22 and Ishido et al. (1998) Biochem. Biophys. Res. Comm.244:35–40, which references are incorporated by reference herein. Thesequence of various genotypes of HCV NS5B are known (Kato et al. (1990)Proc. Natl. Acad. Sci. USA. 87:9524–9528; Webster, G., et al. (2000)Balliere's Clinical Gastroenterology 14, 229–240; van Doom, L. J. (1994)J. of Medical Virology 43, 345–356; Houghton, M. (1996) Hepatitis Cviruses Fields Virology: Third Edition, edited by B. N. Fields, D. M.Knipe, P. M. Howley, et al. Lippincoft-Raven Publishers, Philadelphia,pp. 1035–1058; Lau, J. Y. et. al., J Infect Dis. 1995, 171(2), 281–9).However, NS5B contains sequence motifs that are highly conserved amongall the RNA-dependent RNA polymerases characterized to date.

The present invention provides compounds having antiviral activity. Itis believed that the compounds of the invention will block viralreplication by specifically inhibiting the activity of a viralpolymerase. Viral RNA polymerase is required for the transcription ofgenomic RNA, which process is required for replication of the genome ofan RNA virus. Therefore, inhibition of viral RNA polymerase will inhibitviral replication.

In a first group of preferred embodiments, the compounds useful formodification of a viral RNA-dependent RNA polymerase protein are ofFormula I

wherein:

-   X₁, X₂, X₃ and X₄ are independently N or C—R₁ provided that only one    of X₁, X₂, X₃ and X₄ is N;

R₁ is selected from the group consisting of H, C₁₋₆ alkyl, halogen, —CN,C₁₋₆-alkoxy, C₁₋₆-fluoroalkyl, C₁₋₆-fluroalkoxy and C₁₋₆-alkylthio;

any two adjacent —CR₁ may be taken together to form a fused aromatic orheteroaromatic substituent of two to three rings;

A is selected from the group consisting of —OSO₂-M, —NR₂SO₂-M,—OCR₂R′₂-M and —CR₂R′₂SO_(n)-M;

B is selected from the group —CR₂═N—NH—CO-Z, —CR₂═CR₂NHCO-Z,—NHCR₂═CR′₂CO-Z and -1,2-cyclopropyl-NHCO-Z;

Z is selected from the group -M′, —(CR₂R′₂)_(m)-M′, —O-M′, —NR₂M′, and—(CR₂R′₂)_(m)—O-M′;

R₂ and R₁₂ are independently selected from the group consisting of H andC₁₋₆ alkyl;

M and M′ are independently selected from aryl optionally substitutedwith 1 to 3 R₁, heteroaryl optionally substituted with 1 to 3 R₁ andcycloalkyl of 3 to 8 carbons;

n=0, 1, or 2; and

m=1, 2, 3 or 4;

or a pharmaceutically acceptable salt or prodrug thereof.

Further provided herein are compounds of formula (Ia),

wherein:

A is selected from the group consisting of —OSO₂-M, —NR₂SO2-M,—OCR₂R′₂-M and —CR₂R′₂SO_(n)-M;

Z is selected from the group -M′, —(CR₂R′₂)_(m)-M′, —O-M′, —NR₂-M′, and—(CR₂R′₂)_(m)—O-M′;

R₁ is selected from the group consisting of C₁₋₆ alkyl, halogen, —CN,C₁₋₆-alkoxy, C₁₋₆-fluoroalkyl, C₁₋₆-fluroalkoxy and C₁₋₆-alkylthio;

R₂ and R′₂ are independently selected from the group consisting of H andC₁₋₆ alkyl;

M and M′ are independently selected from aryl optionally substitutedwith 1 to 3 R₁, heteroaryl optionally substituted with 1 to 3 R₁ andcycloalkyl of 3 to 8 carbons;

n=0, 1, or 2; and

m=1, 2, 3 or 4;

or a pharmaceutically acceptable salt or prodrug thereof.

Also provided herein are compounds of formula (Ib),

wherein:

A is selected from the group consisting of —OSO₂-M, —NR₂SO2-M,—OCR₂R′₂-M and —CR₂R′₂ SO_(n)-M;

R₁ is selected from the group consisting of C₁₋₆ alkyl, halogen, —CN,C₁₋₆-alkoxy, C₁₋₆-fluoroalkyl, C₁₋₆-fluroalkoxy and C₁₋₆-alkylthio;

R₂ and R′₂ are independently selected from the group consisting of H andC₁₋₆ alkyl;

M and M′ are independently selected from aryl optionally substitutedwith 1 to 3 R₁, heteroaryl optionally substituted with 1 to 3 R₁ andcycloalkyl of 3 to 8 carbons; and

n=0, 1, or 2; or

a pharmaceutically acceptable salt or prodrug thereof.

In yet another embodiment are provided compounds of formula (Ic),

wherein:

R₁ is selected from the group consisting of C₁₋₆ alkyl, halogen, —CN,C₁₋₆-alkoxy, C₁₋₆-fluoroalkyl, C₁₋₆-fluroalkoxy and C₁₋₆-alkylthio; and

M and M′ are independently selected from aryl optionally substitutedwith 1 to 3 R₁, heteroaryl optionally substituted with 1 to 3 R₁ andcycloalkyl of 3 to 8 carbons;

or a pharmaceutically acceptable salt or prodrug thereof.

In still a further embodiment are compounds of formula (Ic), wherein:

R₁ is selected from the group consisting of C₁₋₆ alkyl, halogen, —CN,C₁₋₆-alkoxy, C₁₋₆-fluoroalkyl, C₁₋₆-fluroalkoxy and C₁₋₆-alkylthio; and

M and M′ are aryl optionally substituted with 1 to 3 R₁;

or a pharmaceutically acceptable salt or prodrug thereof.

In still a further embodiment are compounds of formula (Ic), wherein:

R₁ is selected from the group consisting of C₁₋₆ alkyl, halogen, —CN,C₁₋₆-alkoxy, C₁₋₆-fluoroalkyl, C₁₋₆-fluroalkoxy and C₁₋₆-alkylthio; and

M and M′ are heteroaryl optionally substituted with 1 to 3 R₁;

or a pharmaceutically acceptable salt or prodrug thereof.

Non-limiting examples of the group of preferred compounds are given inTable I.

TABLE I 1.

2-{(E)-[2-(2-pyridin-4-ylacetyl)-hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 2.

2-{(E)-[2-(3-phenylpropanoyl)-hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 3.

2-((E)-{2-[2-(1H-indol-3-yl)-acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzene-sulfonate; 4.

2-{(E)-[2-(2-thien-2-ylacetyl)-hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 5.

2-((E)-{2-[2-(1H-imidazol-4-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 6.

2-{(E)-[2-(2-pyridin-3-ylacetyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 7.

2-((E)-{2-[2-(4-chlorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 8.

2-((E)-{2-[2-(4-fluorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 9.

2-((E)-{2-[2-(3-chloro-4-fluorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 10.

2-((E)-{2-[2-(2-chloro-4-fluorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 11.

2-[(E)-(2-{2-[4-(dimethylamino)phenyl]acetyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 12.

2-((E)-{2-[2-(pentafluorophenyl)acetyl]hydrazono}-methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 13.

2-[(E)-(2-{2-[4-fluoro-3-(trifluoromethyl)phenyl]acetyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 14.

2-[(E)-(2-{2-[3-fluoro-4-(trifluoromethyl)phenyl]acetyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 15.

2-((E)-{2-[2-(2,3,4-trimethoxyphenyl)acetyl]hydrazono}-methyl)phenyl4-(trifluoromethyl)-benzenesulfonate 16.

2-((E)-{2-[2-(2,3,4-trifluorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 17.

2-((E)-{2-[2-(2,4,5-trifluorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 18.

2-((E)-{2-[2-(3,4,5-trifluorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 19.

2-{(E)-[2-(2-{4-[(trifluoromethyl)thio]phenyl}acetyl)hydra-zono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 20.

2-((E)-{2-[2-(2,3,5-trifluorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 21.

2-[(E)-(2-{2-[3-(trifluoromethoxy)phenyl]acetyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 22.

2-((E)-{2-[2-(2,3,6-trichlorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 23.

2-[(E)-(2-{2-[3-fluoro-5-(trifluoromethyl)phenyl]acetyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 24.

2-((E)-{2-[2-(2,3-dimethoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 25.

2-{(E)-[2-(2-{2-[(trifluoromethyl)thio]-phenyl}acetyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 26.

2-[(E)-(2-{2-[4-(methylthio)phenyl]acetyl}hydrazono)methyl]-phenyl4-(trifluoromethyl)benzenesulfonate; 27.

2-((E)-{2-[2-(2,3,6-trifluorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 28.

2-((E)-{2-[2-(2,6-difluorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 29.

2-{(E)-[2-(2-pyridin-2-ylacetyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 30.

2-{(E)-[2-(3-pyridin-3-ylpropanoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 31.

2-((E)-{2-[2-(2,5-difluorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 32.

2-[(E)-(2-{2-[2,5-bis(trifluoromethyl)phenyl]acetyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 33.

2-[(E)-(2-{2-[2-fluoro-6-(trifluoromethyl)phenyl]acetyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 34.

2-[(E)-(2-{2-[4-(trifluoromethyl)phenyl]acetyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 35.

2-[(E)-(2-{2-[3-(trifluoromethyl)phenyl]acetyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 36.

2-((E)-{2-[2-(2-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 37.

2-((E)-{2-[2-(2,5-dimethoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 38.

2-((E)-{2-[2-(3,4-dichlorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 39.

2-[(E)-(2-{2-[3,5-bis(trifluoromethyl)phenyl]acetyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 40.

2-((E)-{2-[2-(2-bromophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 41.

2-((E)-{2-[2-(2-fluorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 42.

2-((E)-{-[2-(2-methylphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 43.

2-((E)-{2-[2-(1,3-benzodioxol-5-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 44.

2-((E)-{2-[2-(4-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 45.

2-{(E)-[2-(2-cyclohexylacetyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;46.

2-{(E)-[2-(4-phenylbutanoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;47.

2-{(E)-[2-(5-phenylpentanoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;48.

2-((E)-{2-[2-(3-fluorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 49.

2-((E)-{2-[2-(5-methoxy-1H-indol-3-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 50.

2-((E)-{2-[2-(3,5-dimethoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 51.

2-((E)-{2-[2-(2,4-dimethoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 52.

2-((E)-{2-[2-(4-bromophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 53.

2-((E)-{2-[2-(3-methoxyphenoxy)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 54.

2-((E)-{2-[3-(2-furyl)propanoyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;55.

2-((E)-{2-[2-(3,4,5-trimethoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 56.

2-[(E)-(2-{2-[2-(benzyloxy)phenyl]acetyl}hydrazono)methyl]-phenyl4-(trifluoromethyl)benzenesulfonate; 57.

2-((E)-{2-[2-(2-phenoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 58.

2-((E)-{2-[3-(3-methoxyphenyl)propanoyl]hydrazono}-methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 59.

2-((E)-{2-[2-(phenylthio)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 60.

2-((E)-{2-[2-(4-iodophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 61.

2-((E)-{2-[2-(5-bromopyridin-3-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 62.

2-((E)-{2-[2-(3-bromophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 63.

2-((E)-{2-[2-(6-chloropyridin-3-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 64.

2-{(E)-[2-(2-phenoxyacetyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;65.

2-((E)-{2-[2-(1-benzofuran-4-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 66.

2-((E)-{2-[2-(2,4,6-trimethoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 67.

2-((E)-{2-[2-(4-ethoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 68.

2-((E)-{2-[2-(2-naphthyl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;69.

2-[(E)-(2-{2-[4-(methylsulfonyl)phenyl]acetyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 70

2-((E)-{2-[2-(3-bromo-4-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 71.

2-{(E)-[2-(1-naphthoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 72.

2-{(E)-[2-(2,5-dichlorobenzoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;73.

2-{(E)-[2-(2-chlorobenzoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 74.

2-{(E)-[2-(2,4-dichlorobenzoyl)hydrazono]methyl}phenyl4-(trifiuoromethyl)benzenesulfonate;75.

benzyl(2E)-2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}oxy)-benzylidene]hydrazinecarboxylate;76.

2-{(E)-[2-(pyridin-3-ylcarbonyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 77.

2-{(E)-[2-(2-nitrobenzoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 78.

2-((E)-{2-[(4-methylphenyl)sulfonyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 79.

2-((E)-{2-[4-(dimethylamino)benzoyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 80.

2-{(E)-[2-(2-bicyclo[2.2.1]hept-2-ylacetyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 81.

2-{(1E)-N-[(3-chlorophenyl)acetyl]ethanehydrazonoyl}-phenyl4-(trifluoromethyl)benzenesulfonate; 82.

2-((E)-{2-[2-(3-pyrazin-2-yl-1,2,4-oxadiazol-5-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 83.

2-[(E)-(2-{[2-(methylthio)pyridin-3-yl]carbonyl}hydrazono)methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 84.

2-{(E)-[2-(2-cyclopentylacetyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;85.

2-{(E)-[2-(2-ethoxybenzoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;86.

2-[(E)-(2-{2-[3-(dimethylamino)phenoxy]acetyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 87.

2-{(E)-[2-(2-methoxybenzoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;88.

2-{(E)-[2-(2-bromobenzoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;89.

2-[(E)-(2-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}hydrazono)methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 90.

2-{(E)-[2-(2-fluorobenzoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 91.

2-((E)-{2-[(1-benzyl-2-oxopyrrolidin-3-yl)carbonyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 92.

2-((E)-{2-[(2-methylpyridin-3-yl)carbonyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 93.

2-((E)-{2-[(3-methylpyridin-2-yl)carbonyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 94.

2-((E)-{2-[2-(1-adamantyl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;95

2-{(E)-[2-(2-tetrahydrofuran-2-ylacetyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;96.

2-{(E)-[2-(2-{3-[(3-methoxybenzyl)amino]phenyl}acetyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 97.

2-[(E)-(2-{2-[3-(1H-pyrrol-1-yl)phenyl]acetyl}hydrazono)methyl]phenyl4-(trifluoromethyl)benzenesulfonate98.

2-((E)-{2-[2-(3-pyrrolidin-1-ylphenyl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate99.

2-((E)-{2-[2-(3-{[4-(acetylamino)benzyl]amino}phenyl)acetyl]-hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate 100.

2-{(E)-[2-(2-methylbenzoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;101.

2-{(E)-[2-(cyclohexylcarbonyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 102.

2-{(E)-[2-(2,6-difluorobenzoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;103.

2-((E)-{2-[2-fluoro-6-(trifluoromethyl)benzoyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 104.

2-((E)-{2-[2-(trifluoromethyl)benzoyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 105.

2-((E)-{2-[(4-ethylphenyl)sulfonyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 106.

2-((E)-{2-[2-(1-methyl-1H-imidazol-4-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 107.

2-((E)-{2-[2-(2-bromo-4,5-dichloro-1H-imidazol-1-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate; 108.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenylbenzenesulfonate; 109.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenylthiophene-2-sulfonate;110.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl2-methylbenzenesulfonate; 111.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl3-methylbenzenesulfonate; 112.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl2-fluorobenzenesulfonate; 113.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl3-fluorobenzenesulfonate; 114.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl3-cyanobenzenesulfonate; 115.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl4-cyanobenzenesulfonate; 116.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl3-chlorobenzenesulfonate; 117.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl4-chlorobenzenesulfonate; 118.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl3,4-difluorobenzenesulfonate;119.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenylnaphthalene-2-sulfonate;120.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl3-chloro-4-fluorobenzenesulfonate; 121.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl4-tert-butylbenzenesulfonate; 122.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl3-(trifluoromethyl)benzenesulfonate; 123.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate; 124.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl2,4-dichlorobenzenesulfonate;125.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl3,4-dichlorobenzenesulfonate;126.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl3,5-dichlorobenzenesulfonate;127.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl3-bromobenzenesulfonate; 128.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl4-bromobenzenesulfonate; 129.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl4-fluorobenzenesulfonate; 130.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl2,5-dimethylbenzenesulfonate;131.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl4-methoxybenzenesulfonate; 132.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl2-chlorobenzenesulfonate; 133.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl2,4-difluorobenzenesulfonate;134.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl4-propylbenzenesulfonate; 135.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl4-isopropylbenzenesulfonate; 136.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenylnaphthalene-1-sulfonate;137.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl2-chloro-4-fluorobenzenesulfonate; 138.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl2,5-dimethoxybenzenesulfonate;139.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl2,5-dichlorobenzenesulfonate;140.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl2-bromobenzenesulfonate; 141.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl2-(trifluoromethoxy)benzenesulfonate; 142.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl4-(trifluoromethoxy)benzenesulfonate; 143.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl3-methoxybenzenesulfonate; 144.

2-{(E)-[2-(2-phenylacetyl)hydrazono]methyl}phenyl1,1′-biphenyl-4-sulfonate;145.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-methylbenzenesulfonate; 146.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 147.

2-((E)-{2-[2-(3-chlorophenyl)acetyl]hydrazono}methyl)-phenyl4-methylbenzenesulfonate; 148.

2-((E)-{2-[2-(3-chlorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 149.

2-((E)-{2-[2-(3,4-dimethoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-methylbenzenesulfonate; 150.

2-((E)-{2-[2-(3,4-dimethoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 151.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-methoxybenzenesulfonate; 152.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl3,4-dimethoxybenzenesulfonate; 153.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl2,5-dimethoxybenzenesulfonate; 154.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl2,4-dimethoxybenzenesulfonate; 155.

4-chloro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-methylbenzenesulfonate; 156.

4-methoxy-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-methylbenzenesulfonate; 157.

2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-4-methylphenyl4-methylbenzenesulfonate; 158.

4-fluoro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-methylbenzenesulfonate; 159.

3; 160.

2-methoxy-6-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-methylbenzenesulfonate; 161.

2-ethoxy-6-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-methylbenzenesulfonate; 162.

1-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-2-naphthyl4-methylbenzenesulfonate; 163.

2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-6-methylphenyl4-methylbenzenesulfonate; 164.

2-((E)-{[(3-chlorophenyl)acetyl]-hydrazono}methyl)-4-fluorophenyl4-methylbenzenesulfonate; 165.

2-methoxy-6-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)-benzenesulfonate; 166.

4-bromo-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}ethyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 167.

4-chloro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 168.

2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-6-methylphenyl4-(trifluoromethyl)benzenesulfonate; 169.

3-bromo-6-methoxy-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 170.

3-methoxy-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 171.

2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-4-methylphenyl4-(trifluoromethyl)benzenesulfonate; 172.

4-fluoro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 173.

2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)-6-methylphenyl4-(trifluoromethyl)benzenesulfonate; 174.

2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)-3-methoxyphenyl4-(trifluoromethyl)benzenesulfonate; 175.

2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)-4-methylphenyl4-(trifluoromethyl)benzenesulfonate; 176.

2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)-4-fluorophenyl4-(trifluoromethyl)benzenesulfonate; 177.

2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-5-methylphenyl4-methylbenzenesulfonate; 178.

2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-5-methylphenyl4-(trifluoromethyl)benzenesulfonate; 179.

2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)-5-methylphenyl4-(trifluoromethyl)benzenesulfonate; 180.

2-chloro-6-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-methylbenzenesulfonate; 181.

3-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-pyridin-2-yl4-methylbenzenesulfonate; 182.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl2,1,3-benzothiadiazole-5-sulfonate; 183.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-pentylbenzenesulfonate; 184.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-propylbenzenesulfonate; 185.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-pyridin-3-yl4-methylbenzenesulfonate; 186.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-isopropoxybenzenesulfonate; 187.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl2,5-dichlorothiophene-3-sulfonate; 188.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl5-methyl-1-phenyl-1H-pyrazole-4-sulfonate; 189.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl[3-(trifluoromethyl)phenyl]methanesulfonate; 190.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl5-bromothiophene-2-sulfonate; 191.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-phenoxybenzenesulfonate; 192.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl5-[5-(trifluoromethyl)isoxazol-3-yl]thiophene-2-sulfonate; 193.

3-chloro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 194.

3-chloro-2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 195.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-acetylbenzenesulfonate; 196.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(1H-pyrazol-1-yl)benzenesulfonate; 197.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(1,3-oxazol-5-yl)benzenesulfonate; 198.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(1,1-dimethylpropyl)benzenesulfonate; 199.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-butoxybenzenesulfonate; 200.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl5-(1,3-oxazol-5-yl)thiophene-2-sulfonate; 201.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl6-phenoxypyridine-3-sulfonate; 202.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(4-fluorophenoxy)benzenesulfonate; 203.

2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-3-methylphenyl4-(trifluoromethyl)benzenesulfonate; 204.

2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-3-methylphenyl4-methylbenzenesulfonate; 205.

2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)-3-fluorophenyl4-methylbenzenesulfonate; 206.

2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)-3-fluorophenyl4-(trifluoromethyl)benzenesulfonate; 207.

3-fluoro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 208.

3-fluoro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-methylbenzenesulfonate; 209.

5-chloro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-methylbenzenesulfonate; 210.

5-chloro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 211.

2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)-5-fluorophenyl4-(trifluoromethyl)benzenesulfonate; 212.

2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)-5-fluorophenyl4-methylbenzenesulfonate; 213.

2-((E)-{2-[2-(3-chlorophenyl)acetyl]hydrazono}methyl)-pyridin-3-yl4-(trifluoromethyl)benzenesulfonate; 214.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-pyridin-3-yl4-(trifluoromethyl)benzenesulfonate; 215.

3-((E)-{2-[2-(3-chlorophenyl)acetyl]hydrazono}methyl)-pyridin-2-yl4-(trifluoromethyl)benzenesulfonate; 216.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl6-morpholin-4-ylpyridine-3-sulfonate; 217.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-(pyridin-3-yloxy)benzenesulfonate; 218.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy}benzenesulfonate; 219.

2-[(1E)-N-(phenylacetyl)ethanehydrazonoyl]phenyl4-(trifluoromethyl)benzenesulfonate;220.

4-fluoro-2-{(1E)-N-[(3-methoxyphenyl)acetyl]ethanehydrazonoyl}-phenyl4-(trifluoromethyl)-benzenesulfonate 221.

2-{(1E)-N-[(3-methoxyphenyl)acetyl]ethanehydrazonoyl}-phenyl4-(trifluoromethyl)benzenesulfonate 222.

5-fluoro-2-{(1E)-N-[(3-methoxyphenyl)acetyl]ethanehydrazonoyl}-phenyl4-(trifluoromethyl)benzenesulfonate 223.

2-{(1E)-N-[(3,4-dichlorophenyl)acetyl]ethanehydrazonoyl}-phenyl4-(trifluoromethyl)benzenesulfonate 224.

methyl3-(4-{[2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenoxy]sulfonyl}phenyl)propanoate;225.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl4-[(2-chloro-1,3-thiazol-5-yl)methoxy]benzenesulfonate; 226.

2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-phenyl5-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]thiophene-2-sulfonate;227.

4-((E)-{2-[2-(3-chlorophenyl)acetyl]hydrazono}methyl)-pyridin-3-yl4-(trifluoromethyl)benzenesulfonate; 228.

4-((E)-{2-[2-(3-chlorophenyl)acetyl]hydrazono}methyl)-pyridin-3-yl4-methylbenzenesulfonate; 229.

4-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-pyridin-3-yl4-methylbenzenesulfonate; 230.

4-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)-pyridin-3-yl4-(trifluoromethyl)benzenesulfonate; 231.

2-(3-chlorophenyl)-N′-[(1E)-(2-{[(4-methylphenyl)sulfonyl]methyl}phenyl)-methylene]acetohydrazide;232.

N′-[(1E)-(2-{[(4-methylphenyl)sulfonyl]methyl}phenyl)-methylene]-2-phenylacetohydrazide;233.

2-(3-methoxyphenyl)-N′-[(1E)-(2-{[(4-methylphenyl)sulfonyl]methyl}phenyl)-methylene]acetohydrazide;234.

N′-{(1E)-[2-(4-methylphenoxy)phenyl]methylene}-2-phenylacetohydrazide;235.

N′-((1E)-{2-[(4-methylbenzyl)oxy]phenyl}methylene)-2-phenylacetohydrazide;236.

2-(3-methoxyphenyl)-N′-((1E)-{2-[(4-methylbenzyl)oxy]phenyl}methylene)-acetohydrazide;237.

N′-((1E)-{2-[(4-tert-butylbenzyl)oxy]phenyl}methylene)-2-pyridin-3-ylacetohydrazide;238.

N′-{(1E)-[2-(1-naphthylmethoxy)phenyl]methylene}-2-phenylacetohydrazide;239.

2-(3-methoxyphenyl)-N′-((1E)-{2-[(4-methylphenyl)sulfonyl]phenyl}methylene)-acetohydrazide;240.

N-(2-{(E)-[(2,5-dichlorobenzoyl)hydrazono]methyl}phenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide;241.

N-[2-((E)-{[(3-bromophenyl)acetyl]hydrazono}methyl)-phenyl]-4-(trifluoromethyl)benzenesulfonamide;242.

N-[2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)-phenyl]-4-(trifluoromethyl)benzenesulfonamide;243.

N-methyl-N-(2-{(E)-[(phenylacetyl)hydrazono]methyl}phenyl)-4-(trifluoromethyl)benzenesulfonamide;244.

N-[2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)-phenyl]-N-methyl-4-(trifluoromethyl)benzenesulfonamide;245.

N-[2-((E)-{[(3-bromophenyl)acetyl]hydrazono}methyl)-phenyl]-N-methyl-4-(trifluoromethyl)benzenesulfonamide;246.

N-[2-((E)-{[(3,4-dimethoxyphenyl)acetyl]hydrazono}methyl)-phenyl]-N-methyl-4-(trifluoromethyl)benzenesuIfonamide;247.

N-methyl-N-(2-{(E)-[(pyridin-3-ylacetyl)hydrazono]methyl}phenyl)-4-(trifluoromethyl)benzenesulfonamide;248.

N-(2-{(E)-[(1,3-benzodioxol-5-ylacetyl)hydrazono]methyl}phenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide;249.

N-(2-{(E)-[(1H-imidazol-4-ylacetyl)hydrazono]methyl}phenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide;250.

2-((E)-[2-[(3-chlorobenzyl)sulfonyl]hydrazono}methyl)-phenyl4-(trifluoromethyl)benzenesulfonate; 251.

2-{(E)-[2-(benzylsulfonyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;252.

2-[(E)-(2-{[4-(trifluoromethyl)benzyl]sulfonyl}hydrazono)-methyl]phenyl4-(trifluoromethyl)benzenesulfonate; 253.

2-(2-{[2-(1,3-benzodioxol-5-yl)acetyl]amino}cyclopropyl)phenyl4-(trifluoromethyl)benzenesulfonate; 254.

2-({[(pyridin-2-ylmethyl)amino]carbonyl}amino)phenyl4-(trifluoromethyl)benzenesulfonate; 255.

2-{(E)-[2-(phenylsulfonyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;256.

2-{(E)-[2-(1-naphthylsulfonyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;

Analysis of the Compounds

The subject compounds and compositions may be demonstrated to havepharmacological activity, e.g, antiviral activity, in in vitro and invivo assays, as known in the art. See for example Behrens, S. E., et. alEMBO J. 15:12–22; Lohmann, V., et. al., 1997, J. Virol. 71:8416–8428;Ferrari, E., et al., 1999. J. Virol. 73:1649–1654; Bealieu, P. L. et.al., WO0204425 A2; Perni, R. B. et. al., WO9833501; which references areincorporated by reference herein.

The subject compounds and compositions are capable of specificallyinhibiting or suppressing a viral infection, e.g., an HCV infection. Anin vivo assessment of the antiviral activity of the compounds of theinvention may be made using an animal model of viral infection, e.g., aprimate model. Cell-based assays may be performed using, e.g, a cellline directly infected with a virus. Cell-based assays for activityagainst a specific viral component, e.g., a polymerase, may also beperformed. Additionally, biochemical or mechanism-based assays, e.g.,transcription assays using a purified protein, Northern blot, RT-PCR,etc., may be performed.

The above-described assays are exemplary and not intended to limit thescope of the invention. The skilled practitioner can appreciate thatmodifications can be made to conventional assays to develop equivalentassays that obtain the same result.

High throughput assays for the presence, absence, quantification, orother properties of particular compounds are well known to those ofskill in the art. Such assays may be adapted to identify compoundscapable of modifying a viral RNA dependent RNA polymerase protein, e.g.,NS5B using functional protein. Preferred assays thus detect enhancementor inhibition of HCV RNA-dependent RNA activity.

Compositions

In view of the antiviral activity associated with the compoundsdescribed above, the present invention further provides pharmaceuticalcompositions comprising one or more of the above compounds incombination with a pharmaceutically acceptable excipient.

In one embodiment, the invention provides the subject compounds combinedwith a pharmaceutically acceptable excipient such as sterile saline orother medium, water, gelatin, an oil, etc. to form pharmaceuticallyacceptable compositions. The compositions and/or compounds may beadministered alone or in combination with any convenient carrier,diluent, etc. and such administration may be provided in single ormultiple dosages. Useful carriers include solid, semi-solid or liquidmedia including water and non-toxic organic solvents.

In another embodiment, the invention provides the subject compounds inthe form of a prodrug, which can be metabolically or chemicallyconverted to the subject compound by the recipient host. A wide varietyof prodrug derivatives are known in the art such as those that rely onhydrolytic cleavage or oxidative activation of the prodrug.

The compositions may be provided in any convenient form, includingtablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, suppositories, etc. As such, the compositions, inpharmaceutically acceptable dosage units or in bulk, may be incorporatedinto a wide variety of containers. For example, dosage units may beincluded in a variety of containers including capsules, pills, etc.

Methods of Use

In yet another aspect, the present invention provides novel methods forthe use of the foregoing compounds and compositions. In particular, theinvention provides novel methods for treating or preventing viralinfections, e.g., HCV infection. The invention also provides novelmethods for treating or preventing diseases resulting from, in whole orin part, viral infections, preferably diseases resulting from, in wholeor in part, infection, such as hepatitis C, cirrhosis, chronic liverdisease and hepatocellular carcinoma. The methods typically involveadministering to a patient an effective amount of one or more of thesubject compounds or compositions.

The compositions may be advantageously combined and/or used incombination with other antiviral agents which are either therapeutic orprophylactic agents, and different from the subject compounds. Thecompositions may also be advantageously combined and/or used incombination with agents that treat conditions often associated with theviral infections that are sensitive to the present compounds, such asanti-HIV agents or immunosuppressive agents. In many instances,administration in conjunction with the subject compositions enhances theefficacy of such agents. Accordingly, the present compounds, whencombined or administered in combination with other antiviral agents, canbe used in dosages which are less than the expected amounts when usedalone, or less than the calculated amounts for combination therapy.

Exemplary treatment options for hepatitis C(HCV) include interferons,e.g., interferon alfa-2b, interferon alfa-2a, and interferon alfacon-1.Less frequent interferon dosing can be achieved using pegylatedinterferon (interferon attached to a polyethylene glycol moiety whichsignificantly improves its pharmacokinetic profile). Combination therapywith interferon alfa-2b (pegylated and unpegylated) and ribavarin hasalso been shown to be efficacious for some patient populations. Otheragents currently being developed include RNA replication inhibitors,antisense agents, therapeutic vaccines, protease ihibitors, helicaseinhibitors and antibody therapy (monoclonal and polyclonal).

The compounds and compositions of the present invention may also be usedwith agents that enhance the body's immune system, including low-dosecyclophosphamide, thymostimulin, vitamins and nutritional supplements(e.g., antioxidants, including vitamins A, C, E, beta-carotene, zinc,selenium, glutathione, coenzyme Q-10 and echinacea), and vaccines, e.g.,the immunostimulating complex (ISCOM), which comprises a vaccineformulation that combines a multimeric 5 presentation of antigen and anadjuvant.

The compositions and compounds of the invention and the pharmaceuticallyacceptable salts thereof can be administered in any effective way suchas via oral, parenteral or topical routes. Generally, the compounds areadministered in dosages ranging from about 2 mg up to about 2,000 mg perday, although variations will necessarily occur depending on the diseasetarget, the patient, and the route of administration. Preferred dosagesare administered orally in the range of about 0.05 mg/kg to about 20mg/kg, more preferably in the range of about 0.05 mg/kg to about 2mg/kg, most preferably in the range of about 0.05 mg/kg to about 0.2 mgper kg of body weight per day.

Preparation of the Compounds

The compounds of this invention can be prepared by one or more of thefollowing schemes described below.

EXAMPLES

The following examples further illustrate the preparation and analysisof compounds of the invention. The examples are illustrative only andnot intended to limit the scope of the invention in any way. Reagentsand solvents can be obtained from commercial sources such as AldrichChemical Co. (Milwaukee, Wis., USA). All commercially obtained reagentsare used as received without further purification. Solvents are used asreceived or dried over appropriate drying agents and distilled. ProtonNMR experiments are carried out on a Bruker 400 MHz spectrometer, andchemical shifts are reported in ppm downfield from internal TMS. CarbonNMR experiments are carried out on a Bruker 500 MHz spectrometer, andchemical shifts are reported in ppm relative to the central line ofdeuteriochloroform at 77.0 ppm. Low resolution mass spectra (ESI) areobtained on a Micromass Platform C spectrograph. Low resolution massspectra (EI) and high resolution mass spectra (FAB), as well as IRspectra and elemental analyses are conducted by the Pharmacia analyticallaboratory. Flash column chromatography is carried out on Biotage 40prepacked columns, while preparative TLC is carried out on Merck silicagel F₂₅₄-coated plates with 0.25 mm or 0.5 mm silica layers. Unlessotherwise noted, reactions are carried out in dry glassware under anitrogen atmosphere.

The aromatic aldehydes used in the examples were prepared according toprocedures described in the literature as listed below.

-   -   3-chloro-2-hydroxybenzaldehyde; Casiraghi, Giovanni; Casnati,        Giuseppe; Puglia, Giuseppe; Sartori, Giovanni; Terenghi,        Giuliana; J. Chem. Soc. Perkin Trans. 1, 1980; 1862–1865.    -   5-chloro-2-hydroxybenzaldehyde; Hepworth, John D.; Jones, Terry        K.; Livingstone, Robert; Tetrahedron; 37; 15; 1981; 2613–2616.    -   4-fluoro-2-hydroxybenzaldehyde; Aldred, Robert; Johnston,        Robert; Levin, Daniel; Neilan, James; J. Chem. Soc. Perkin        Trans. 1; 13; 1994; 1823–1832.    -   5-fluoro-2-hydroxybenzaldehyde; Aldred, Robert; Johnston,        Robert; Levin, Daniel; Neilan, James; J. Chem. Soc. Perkin        Trans. 1; 13; 1994; 1823–1832.    -   5-methyl-2-hydroxybenzaldehyde; Komiyama, Makoto; Hirai,        Hidefumi; J. Amer. Chem. Soc.; 105; 7; 1983; 2018–2021.    -   2-hydroxynicotinaldehyde; Guilbert; Johnson; Biochemistry; 10;        1971; 2313.    -   3-hydroxypyridine-2-carboxaldehyde; Wang, Pou-Hsiung; Keck,        James, G.; Lien, Eric J.; Lai, Michael M. C.; J. Med. Chem.; EN;        33; 2; 1990; 608–614.

Example 1 According to Scheme 12-((E)-{2-[2-(1,3-benzodioxol-5-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate [PHA-818736]

A solution of 4-(trifluoromethyl)benzenesulphonyl chloride (2.4 g, 9.84mmol) in pyridine (40 mL) is cooled to 0° C. Salicylaldehyde (1.44 g,11.8 mmol) is added and stirred overnight. Water and ethyl acetate areadded to the reaction and shaken. The organic layer is washed withdilute HCl (0.1 N×2), H₂O, bicarbonate solution, H₂O and dried withsodium sulfate. The organic layer is evaporated to dryness to give ayellow solid, which is recrystallized from ether/hexane to give2-formylphenyl 4-(trifluoromethyl)benzenesulfonate as a yellow powder(1.70 g, 52%).

A solution of 2-formylphenyl 4-(trifluoromethyl)benzenesulfonate (1.7 g,5.1 mmol) in warm ethanol (100 mL) is added dropwise over 1 hour into asolution of hydrazine (6 equiv) in ethanol (5 mL). The reaction isstirred at room temperature overnight at which time the solvent isevaporated to dryness. The crude product is recrystallized fromCH₂Cl₂/hexane to remove a dimer by-product. An 89% yield of2-[hydrazonomethyl]phenyl 4-(trifluoromethyl)benzenesulfonate (4.65 g)is obtained.

A solution of 2-[hydrazonomethyl]phenyl4-(trifluoromethyl)benzenesulfonate (150 mg, 0.44 mmol) and1,3-benzodioxol-5-ylacetic acid (1.2 equiv) in DMF (1 mL) is treatedwith a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (EDC) (167 mg, 0.87 mmol) and 4-dimethylaminopyridine(DMAP) (106 mg, 0.87 mmol) in CH₂Cl₂ (10 mL). The solution is shakenovernight on an orbital shaker. The solution is evaporated to drynessusing a speed. Water is added to the mixture, which is then sonicated togive a solid. The solid is filtered and washed with a large amount ofwater. A small amount of methanol is added and the mixture sonicated.The resulting solid is filtered and washed with more methanol to yieldpure 2-((E)-{2-[2-(1,3-benzodioxol-5-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate. The yield is 169 mg, 77%. ¹H NMR(400 MHz, DMSO) □ 11.48 (2s, 1H), 8.01 (m, 6H), 7.12 (m, 6H), 5.99 (2s,2H), 3.62 (2s, 2H). ESI− for C₂₃H₁₇F₃N₂O₆S, m/z 505, (M−H)−.

Example 2 According to Scheme 22-{[2-(2-arylacetyl)hydrazono]methyl}phenyl4-trifluoromethyl)benzenesulfonate [PHA-813673]

A solution of 4-imidazoleacetic acid (4.2 g, 26 mmol) in methanol (150mL) is treated with HCl in dioxane (5 mL). The mixture is heated at 60°C. overnight. The solution is evaporated to give a white solid, which isthen recrystallized from ether/hexane to yield 4-imidazoleacetic acidmethyl ester hydrochloride. The yield is 4.5 g, 98%.

To a solution of 4-imidazoleacetic acid methyl ester hydrochloride (3.95g, 22.4 mmol) in ethanol (150 ml) is added N,N-diisopropylethylamine(2.90 g, 16.6 mmol) and hydrazine (1.79 g, 36 mmol). The solution isrefluxed at 70° C. overnight. The solution is concentrated andrecrystallized from methanol to give 4-imidazoleacetic acid hydrazide asa white solid. The yield is 2.46 g, 78%.

A solution of 2-formylphenyl 4-(trifluoromethyl)benzenesulfonate (6.5 g,19.7 mmol) in ethanol (100 ml) is added to a solution of4-imidazoleacetic acid hydrazide (18 mmol) in ethanol (200 mL). Acatalytic amount of HCl in dioxane (3 mL) is added and the mixture isstirred at room temperature overnight. The precipitate that forms isremoved by filtration. The filtrate is concentrated and chromatographedon silica eluting with 5% (2M ammonia in methanol)/CH₂Cl₂ to give2-((E)-{2-[2-(1H-imidazol-4-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate as a white solid. The yield is 3.1g, 38%. ¹H NMR (400 MHz, DMSO) d 11.94 (s, 1H), 11.48 (2s, 1H), 8.02 (m,6H), 7.21 (m, 5H), 3.64 (2 s, 2H). ESI+ for C₁₉H₁₅F₃N₄O₄S, m/z 453,(M+H)+.

Example 3 According to Scheme 32-((E)-{2-[2-(3-chlorophenyl)acetyl]hydrazono}methyl)phenyl4-methylbenzenesulfonate [PHA-804389]

To a solution of 2-(3-chlorophenyl)acetohydrazide (1 g, 5.42 mmol) inabsolute EtOH 80 mL and acetic acid 2 mL was added salicylaldehyde(1.323 g, 10.83 mmol). The reaction was stirred at room temperate overnight. The reaction mixture was then filtered. The solid was washed withhexane and EtOH. The yield is 1.4 g of2-(3-chlorophenyl)-N′-[(1E)-(2-hydroxyphenyl)methylidene]acetohydrazide(90%).

To 1 mL pyridine solution of2-(3-chlorophenyl)-N′-[(1E)-(2-hydroxyphenyl)methylidene]acetohydrazide(86.6 mg, 0.3 mmol) was added 1 mL DCM solution of4-methylbenzenesulfonyl chloride (114 mg, 0.6 mmol). The reaction wasshaken over night and the solvent was removed by evaporation. Water wasadded to the mixture, sonicated to a fine powder and filtered. Thepowder was washed with more water. The dried powder is triturated withMeOH to give 1.2-((E)-{2-[2-(3-chlorophenyl)acetyl]hydrazono}methyl)phenyl4-methylbenzenesulfonate in 88% yield. ¹H NMR (400 MHz, DMSO) □11.64–11.46 (2s, 1H), 7.98 (m, 2H), 7.71 (m, 2H), 7.28 (m, 8H), 7.12 (m,1H), 3.95–3.58 (2s, 2H), 2.35–2.30 (2s, 3H). ESI− for C₂₂H₁₉ClN₂O₄S:m/z=441 (M−H)−.

Example 4 According to Scheme 4N′-[(1E)-(2-{[(4-methylphenyl)sulfonyl]methyl}phenyl)methylene]-2-phenylacetohydrazide[PHA-817139]

To a premixed solution of 2-methylbenzoic acid (7.5 mmol), EDCl (1.5mmol) and DMAP (3.0 mmol) in DMA 40 mL and DCM 13 mL is addeddimethylhydroxylamine hydrochloride (1.5 mmol). The reaction is stirredat room temperate over night. The reaction mixture is then filtered. Thefiltrate is diluted with EtOAc and washed with water, 10% NaHSO₄ andbrine. The solution is dried over Na₂SO₄ and the solvent is evaporated.A light yellow oil N-methoxy-N,2-dimethylbenzamide is obtained in 80%yield.

To a solution of N-methoxy-N,2-dimethylbenzamide (1.67 mmol) in CCl₄ isadded NBS (1.67 mmol) and AIBN (cat. amount). The refluxed mixture isirradiated for 45 min. 1.11 mmol of NBS and a cat. amount of AIBN areadded to the mixture and the mixture is then refluxed and irradiated foranother 45 min. The reaction mixture is cooled down and filtered. Thesolution is dried over Na₂SO₄ and the solvent is evaporated. The crudeoil, 2-(bromomethyl)-N-methoxy-N-methylbenzamide, is used as obtained. Asolution of 2-(bromomethyl)-N-methoxy-N-methylbenzamide (1.67 mmol) andp-toluenesulfinic acid sodium salt dihydrate in 10 mL DMA is heated to100° C. for 5 hr. The reaction mixture is diluted with EtOAc and washedwith brine, 10% NaHSO₄ and brine again. The solution is dried overNa₂SO₄ and the solvent is evaporated. The crude material is purified byflash column chromatography to give a 48% yield of a colorless oil,N-methoxy-N-methyl-2-{[(4-methylphenyl)sulfonyl]methyl}benzamide.

To a solution ofN-methoxy-N-methyl-2-{[(4-methylphenyl)sulfonyl]methyl}benzamide (0.645mmol) in 5 mL THF at −78° C. is added 1.0 M solution of LiAlH₄ in THF(0.709 mmol) slowly with stirring. The reaction is stirred at −78° C.for 1 hr and gradually warmed up to RT. The reaction mixture is dilutedwith EtOAc and washed with H₂O. The solution is dried over Na₂SO₄ andthe solvent is evaporated to give a quantitative yield of2-{[(4-methylphenyl)sulfonyl]methyl}benzaldehyde.

To a solution of-phenylacetic acid hydrazide (0.24 mmol) in absoluteEtOH 10 mL and acetic acid 0.4 mL is added2-{[(4-methylphenyl)sulfonyl]methyl}benzaldehyde (0.22 mmol). Thereaction is stirred at room temperate for 2.5 hr with white pptformation. The reaction mixture is then filtered. The solid istriturated with MeOH to giveN′-[(1E)-(2-{[(4-methylphenyl)sulfonyl]methyl}phenyl)methylene]-2-phenylacetohydrazidein 78% yield. ¹H NMR (400 MHz, DMSO-d₆) □ 11.50–11.25 (2s, 1H),8.22–8.13 (2s, 1H), 7.79 (m, 1H), 7.56 (m, 2H), 7.31 (m, 10H), 4.93–4.80(2s, 2H), 3.95–3.57 (2s, 2H), 2.36–2.31 (2s, 3H). ESI− for C₂₃H₂₂N₂O₃S,m/z 405 (M−H)−.

Example 5a According to Scheme 5aN′-{(1E)-[2-(4-methylphenoxy)phenyl]methylene}-2-phenylacetohydrazide[PHA815012]

To a solution of 2-fluorobenzaldehyde (3.54 g, 28.5 mmol) in DMA (20 mL)is added p-cresol (3.08 g, 28.5 mmol) and K₂CO₃ (4.72 g, 34.2 mmol), andthe reaction mixture is heated to 150° C. for 12 h. Once complete, thereaction mixture is cooled to room temperature and diluted with water(100 mL) prior to being poured into a separatory funnel containing ethylacetate (250 mL). The organic layer is separated, washed with brine (2×)and dried over sodium sulfate prior to concentration. The crude productis purified by column chromatography (5% ethyl acetate in hexanes) toafford 2-(4-methylphenoxy)-benzaldehyde (3.05 g, 50%) as a light yellowoil.

To a solution of 2-(4-methylphenoxy)-benzaldehyde (500 mg, 2.36 mmol) inEtOH (10 mL) is added phenyl acetic hydrazide (336 mg, 2.36 mmol) andthe reaction is heated to 80° C. for 1 h. While cooling a whiteprecipitate forms, and this solid is isolated by filtration and washedwith portions of EtOH and Et₂O. This solid is dried under vacuum toprovideN′-{(1E)-[2-(4-methylphenoxy)phenyl]methylene)}2-phenylacetohydrazide(432 mg, 22%). ¹H-NMR (400 MHz, DMSO-d₆) 11.70–11.55 (m, 1H), 8.51–8.33(m, 1H), 8.00–7.92 (m, 1H), 7.42–7.19 (m, 9H), 6.91–6.85 (m, 3H),3.98–3.43 (m, 2H), 2.29 (s, 3H). ESI+ for C₂₂H₂₀N₂O_(2:) m/z=345 (M+H)+.

Example 5b According to Scheme 5bN′-{(1E)-[2-(1-naphthylmethoxy)phenyl]methylene}-2-phenylacetohydrazide[PHA-846631]

To a solution of 2-hydroxybenzaldehyde (2.30 g, 18.8 mmol) in DMF (20mL) is added 1-(chloromethyl)-naphthalene (3.36 mL, 22.6 mmol) and K₂CO₃(3.11 g, 22.6 mmol), and the reaction mixture is heated to 100° C. for12 h. Once complete, the reaction mixture is cooled to room temperatureand diluted with water (100 mL) prior to being poured into a separatoryfunnel containing ethyl acetate (250 mL). The organic layer isseparated, washed with brine (2×) and dried over sodium sulfate prior toconcentration. The crude product is purified by column chromatography(5% ethyl acetate in hexanes) to afford2-(1-naphthylmethoxy)benzaldehyde (2.13 g, 43%) as a light yellow oil.

To a solution of 2-(1-naphthylmethoxy)benzaldehyde (300 mg, 1.14 mmol)in EtOH (10 mL) is added phenyl acetic hydrazide (172 mg, 1.14 mmol) andthe reaction is heated to 80° C. for 1 h. While cooling a whiteprecipitate forms, and this solid is isolated by filtration and washedwith portions of EtOH and Et₂O. This solid is dried under vacuum toprovideN′-{(1E)-[2-(1-naphthylmethoxy)phenyl]methylene-2-phenylacetohydrazide(254 mg, 57%). ¹H-NMR (400 MHz, DMSO-d₆) 11.60–11.55 (m, 1H), 8.43–8.38(m, 1H), 8.11–7.74 (m, 4H), 7.60–7.56 (m, 2H), 7.44–7.42 (m, 2H),7.31–7.21 (m, 4H), 7.05–7.04 (m, 1H), 5.65–5.63 (m, 2H), 3.96 (s, 1H),3.54 (s, 1H), 3.34 (s, 3H). ESI+ for C₂₆H₂₂N₂O₂ m/z 395 (M+H)+.

Example 5c According to Scheme 5c2-(3-methoxyphenyl)-N′-((1E)-{2-[(4-methylphenyl)sulfonyl]phenyl}methylene)acetohydrazide[PHAB15159]

To a solution of 2-fluorobenzaldehyde (12.4 g, 100 mmol) in DMSO (75 mL)is added p-toluenesulfinic acid sodium salt (19.6 g, 110 mmol), and thereaction mixture is heated to 100° C. for 16 h. Once complete, thereaction mixture is cooled to room temperature and poured onto ice. Theproduct is then isolated as a white solid by filtration to afford2-[(4-methylphenyl)sulfonyl]benzaldehyde (10.1 g, 39%).

To a solution of 2-[(4-methylphenyl)sulfonyl]benzaldehyde (500 mg, 1.92mmol) in EtOH (10 mL) is added 2-(3-methoxyphenyl)acetohydrazide (329mg, 1.92 mmol) and the reaction is heated to 80° C. for 1 h. Whilecooling a white precipitate forms, and this solid is isolated byfiltration and washed with portions of EtOH and Et₂O. This solid wasdried under vacuum to provide2-(3-methoxyphenyl)-N′-((1E)-{2-[(4-methylphenyl)sulfonyl]phenyl}methylene)acetohydrazide(313 mg, 39%). ¹H-NMR (400 MHz, DMSO-d₆) 12.00–11.85 (m, 1H), 8.95–8.80(m, 1H), 8.16–8.10 (m, 1H), 7.99–7.81 (2H), 7.72–7.65 (m, 2H), 7.42–7.37(m, 2H), 7.27–7.16 (m, 1H), 6.93–6.76 (m, 4H), 3.92–3.36 (m, 5H), 2.35(s, 3H). ESI+ for C₂₃H₂₂N₂O₄S, m/z: 423, (M+H)+.

Example 6a According to Scheme 6aN-[2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)phenyl]-4-(trifluoromethyl)benzenesulfonamide[PHA-813900]

A mixture of THF (20 mL), water (8 mL), sodium bicarbonate (1.0 g), and4-dimethylaminopyridine (0.5 g) is treated with 2-aminobenzyl alcohol(2.0 g, 16 mmol) and a solution of 4-(trifluoromethylbenzene)sulfonylchloride (3.0 g, 12 mmol) in THF (4 mL). The reaction is stirred 1 h atroom temperature, concentrated, and partitioned between ethyl acetateand 3 N HCl. The organic layer is dried, concentrated, and purified onsilica gel in ethyl acetate-methylene chloride mixtures. A yield of 47%(2.5 g) is obtained. The productN-[2-(hydroxymethyl)phenyl]-4-(trifluoromethyl)benzenesulfonamide iscrystallized from methylene chloride-hexane.

A solution ofN-[2-(hydroxymethyl)phenyl]-4-(trifluoromethyl)benzenesulfonamide (3 g,9 mmol) in methylene chloride is treated with manganese (IV) oxide (6.6g, 76 mmol) at room temperature overnight. The reaction is filtered andthe product, N-(2-formylphenyl)-4-(trifluoromethyl)benzenesulfonamide,is purified on silica gel eluting with ethyl acetate-methylene chlorideand used as obtained.

To a solution ofN-(2-formylphenyl)-4-(trifluoromethyl)benzenesulfonamide (0.67 mmol) inethanol (5 mL) is added to hydrazine hydrate (47 mg, 1.5 mmol) inethanol (3 mL). The reaction is stirred at room temperature 50 minutes.The reaction is decanted and evaporated, and the product,N-{2-[(E)-hydrazonomethyl]phenyl}-4-(trifluoromethyl)benzenesulfonamide,is used without further purification.

A flask is charged with (3-chlorophenyl)acetic acid (0.34 mmol),4-dimethylaminopyridine (0.66 mmol), a solution ofN-{2-[(E)-hydrazonomethyl]phenyl}-4-(trifluoromethyl)benzenesulfonamide(0.33 mmol) in N,N-dimethylacetamide (1 mL), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.33 mmol).The reaction is stirred at room temperature for 18 hours. The reactionis worked up either by adding water and obtaining a solid precipitate,or by evaporating the reaction mixture. The product is purified onsilica gel with ethyl acetate-methylene chloride mixtures. Obtained a60% yield ofN-[2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)phenyl]-4-(trifluoromethyl)benzenesulfonamide.¹H NMR (400 MHz, CDCl₃)(mixture of geometric isomers) d 3.73&4.17(2s,2H); 7.16 (m); 7.36 (m); 7.47 (s); 7.60m; 7.66 (m); 7.75 (m); 7.89 (s);7.96 (m); 8.06 (m); 9.62 (bs); 10.80 (bs). ESI− for C₂₂H₁₇ClF₃N₃O₃S: m/z=494 (M−H)−.

Example 6b According to Scheme 6bN-[2-((E)-[(3,4-dimethoxyphenyl)acetyl]hydrazono}methyl)phenyl]-N-methyl-4-(trifluoromethyl)benzenesulfonamide[PHA-820387]

A solution of N-(2-formylphenyl)-4-(trifluoromethyl)benzenesulfonamide(2.2 g, 6.6 mmol) in methanol (11 mL) is treated with a solution ofsodium hydroxide (275 mg, 6.9 mmol) in water (2.4 mL). To this is addeddimethylsulfate (0.64 mL, 6.8 mmol). The reaction is stirred at rtovernight, evaporated, and chromatographed on silica gel in 5% and 10%ethyl acetate-methylene chloride. The product fractions are furtherpurified by crystallization from toluene-hexane to affordN-(2-formylphenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide in 68%yield.

A solution ofN-(2-formylphenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide (0.40g, 1.2 mmol) in ethanol (13 mL) is treated with hydrazine monohydrate(69 □L, 1.6 mmol). The reaction is stirred at rt overnight. The reactionis concentrated, taken up in ether-hexane, filtered and evaporated. An87% yield (0.37 g) ofN{2-[hydrazonomethyl]phenyl}-N-methyl-4-(trifluoromethyl)benzenesulfonamideis obtained.

A flask is charged with (3,4-dimethoxyphenyl)acetic acid (0.34 mmol),4-dimethylaminopyridine (0.66 mmol), a solution ofN-{2-[hydrazonomethyl]phenyl}-N-methyl-4-(trifluoromethyl)benzenesulfonamide(0.33 mmol) in N,N-dimethylacetamide (1 mL), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.33 mmol).The reaction is stirred at room temperature for 18 hours. The reactionis worked up by evaporating the reaction mixture. The product ispurified on silica gel with ethyl acetate-methylene chloride mixtures ormethanol-methylene chloride mixtures. A 58% yield ofN-[2-((E)-{[(3,4dimethoxyphenyl)acetyl]hydrazono}methyl)phenyl]-N-methyl-4-(trifluoromethyl)benzenesulfonamideis obtained. ¹H NMR (400 MHz, CDCl3) (mixture of geometric isomers) d3.25 (s); 3.90 (2s); 4.10 (m); 6.58 (m); 6.87 (m); 6.96 (m); 7.45 (m);7.82 (m); 8.20 (m); 8.29 (m); 8.90&8.96 (2bs). ESI− for C₂₅H₂₄F₃N₃O₅S:m/z=534 (M−H)−.

Example 7 According to Scheme 72-{(E)-[2-(benzylsulfonyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate. [PHA-820539]

Into a round-bottomed flask are placed hydrazine monohydrate (0.29 mL,6.06 mmol) and ethanol (5 mL). To this flask a solution of2-formylphenyl 4-(trifluoromethyl)benzenesulfonate (200 mg, 0.606 mmol)in ethanol (5 mL) is added dropwise over 1 h. The resulting mixture isstirred at rt for 16 h. The solution is concentrated and the productrecrystallized form Et₂O/Hexane to afford product that is used directlyin the next step. The yield is 200 mg of 2-[(E)-hydrazonomethyl]phenyl4-(trifluoromethyl)benzenesulfonate, 96%.

Into a glass vial are placed 2-[(E)-hydrazonomethyl]phenyl4-(trifluoromethyl)benzenesulfonate (187 mg, 0.543 mmol)α-toluenesulfonyl chloride (114 mg, 0.597 mmol), and pyridine (5 mL).The resulting mixture is shaken at rt for 16 h. The solution isconcentrated and EtOAc is added and the solution washed with water. Theorganic layer is dried (Na₂SO₄), concentrated, and isolated bypreparative thin layer chromatography (gradient: 20% EtOAc/Hexane 40%EtOAc/Hexane). The yield is 63 mg of2-{(E)-[2-(benzylsulfonyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate, 23%. ¹H NMR (400 MHz, DMSO-d₆): □11.51(s, 1H), 8.14–8.12 (m, 2H), 8.09–8.07 (m, 2H), 7.97 (s, 1H),7.93–7.90 (m, 1H), 7.52–7.43 (m, 2H), 7.38–7.30 (m, 5H), 7.13–7.10 (m,1H), 4.55 (s, 2H). HRMS for C₂₁H₁₇F₃N₂O₅S₂ m/z 499.0609 (M+H)+.

Example 8 According to Scheme 82-((1R,2S)-2-{[2-(1,3-benzodioxol-5-yl)acetyl]amino}cyclopropyl)phenyl4-(trifluoromethyl)benzenesulfonate [PHA-828238]

A dry, air-free, ice-cold solution of 2-formylphenyl4-(trifluoromethyl)-benzenesulfonate (2.0 g, 6.1 mmol) in THF (7 mL) istreated with 6.8 mL of 1 M (trimethylsilylmethyl)magnesium chloride indiethyl ether. The reaction is stirred 30 minutes. Thionyl chloride (0.5mL, 6.9 mmol) is added and the reaction is stirred at 0° C. for 1 h. Thereaction is quenched with ice and extracted with ethyl acetate. Theproduct is purified on silica gel in methylene chloride. A yield of 1.8g of 2-vinylphenyl 4-(trifluoromethyl)benzenesulfonate is obtained.

A mixture of 2-vinylphenyl 4-(trifluoromethyl)benzenesulfonate (1.8 g,5.5 mmol) and ethyl diazoacetate (0.70 mL, 6.7 mmol) under argon isheated at 135° C. for 90 min. The product is purified on silica gel inmethylene chloride and ethyl acetate-methylene chloride mixtures. Theproduct, ethyl2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}oxy)phenyl]cyclopropanecarboxylate,is obtained as a mixture of isomers. A yield of 50% is obtained.

A solution of ethyl2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}oxy)phenyl]-cyclopropanecarboxylate(0.84 g, 2.0 mmol) in THF (2 mL) is treated under an inert atmospherewith a 2 M solution of borane-methyl sulfide complex in THF (1 mL). Thereaction is heated to 70° C. for 1 h, and stirred at room temperatureovernight. The reaction is worked up by partitioning between ethylacetate and 1 N HCl. The organic layer is dried and evaporated. Theproduct, 2-[2-(hydroxymethyl)cyclopropyl]phenyl4-(trifluoromethyl)benzenesulfonate, is obtained as a mixture ofisomers. A yield of 93% is obtained.

A mixture of 2-[2-(hydroxymethyl)cyclopropyl]phenyl4-(trifluoromethyl)-benzenesulfonate (0.70 g, 1.9 mmol), carbontetrachloride (2.5 mL), acetonitrile (2.5 mL), water (3.8 mL), sodiumperiodate (1.8 g, 8.4 mmol) and ruthenium choride hydrate (75 mg, 0.4mmol) is stirred at room temperature overnight. The reaction ispartitioned between ethyl acetate and dilute HCl. The organic layer isfiltered through anhydrous sodium sulfate, evaporated and purified onsilica gel in ethyl acetate-methylene chloride-acetic acid mixtures. Theproduct,2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}oxy)phenyl]cyclopropanecarboxylicacid, is obtained as a mixture of isomers. A yield of 95% is obtained.

A mixture of2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}oxy)phenyl]-cyclopropanecarboxylicacid (0.25 g, 0.64 mmol), t-butyl alcohol (0.76 g, 10.3 mmol),diphenylphosphoryl azide (0.32 g, 1.2 mmol), and triethylamine (0.22 g,2.2 mmol) is heated under an inert atmosphere to 90° C. for 3 hours,then the reaction is allowed to stir at room temperature overnight. Thereaction is diluted with ethyl acetate and washed with 1 N HCl, 5%sodium bicarbonate solution, and brine. The dried, concentrated materialis purified by chromatography on silica gel in ethyl acetate-hexanemixtures. The product having trans stereochemistry,2-{2-[(tert-butoxycarbonyl)amino]cyclopropyl}phenyl4-(trifluoromethyl)benzenesulfonate, is obtained as the less polarcomponent in 50% yield. It is further purified by crystallization frommethylene chloride-hexane.

A solution of 2-{2-[(tert-butoxycarbonyl)amino]cyclopropyl}phenyl4-(trifluoromethyl)benzenesulfonate (0.09 g, 0.2 mmol) in methylenechloride (1 mL) is treated with trifluoroacetic acid (0.1 mL) at roomtemperature for 2 hours. The reaction is evaporated in vacuo to a whitesolid. The solid is treated with N,N-dimethylacetamide (0.3 mL), andtriethylamine (27 □L, 0.2 mmol). A mixture of3,4-(methylenedioxy)phenylacetic acid (39 mg, 0.22 mmol),4-dimethylaminopyridine (27 mg, 0.22 mmol), and N,N-dimethylacetamide(0.1 mL) is added to the reaction, followed by the addition of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (42 mg, 0.22 mmol). Thereaction is stirred at room temperature overnight. After work-up withethyl acetate-hexane-water, the dried, evaporated residue is purified onsilica gel in ethyl acetate-methylene chloride mixtures. The product,2-((1R,2S)-2-{[2-(1,3-benzodioxol-5-yl)acetyl]amino}cyclopropyl)phenyl4-(trifluoromethyl)-benzenesulfonate, is recrystallized frommethanol-water. A yield of 80% is obtained. ¹H NMR (400 MHz, CDCl3) d1.15 (m, 1H); 1.25 (m, 1H); 2.07 (m, 1H); 2.80 (m, 1H); 3.50 (s, 2H);5.97 (m, 3H); 6.78 (m, 4H); 7.05 (m, 1H); 7.13 (m, 1H); 7.21 (m, 1H);7.85 (m, 2H); 8.02 (m, 2H). ESI+ for C₂₅H₂₀F₃NO₆S m/z=520 (M+H)+.

Example 9 According to Scheme 92-({[(pyridin-2-ylmethyl)amino]carbonyl}amino)phenyl4-(trifluoromethyl)benzenesulfonate [PHA-832262]

2-Aminophenyl 4-(trifluoromethyl)benzenesulfonate (1.00 mmol, 317 mg) isdissolved in 8 ml CHCl₃. 4-Nitrophenyl chloroformate (1.00 mmol, 200 mg)and pyridine (1.00 mmol, 81 μl) are added to the solution. The reactionmixture is heated to 45° C. for an hour. After removing the solvent,2-{[(4-nitrophenoxy)carbonyl]amino}phenyl4-(trifluoromethyl)benzenesulfonate is used directly without furtherpurification.

2-{[(4-nitrophenoxy)carbonyl]amino}phenyl4-(trifluoromethyl)-benzenesulfonate (0.25 mmol, 120 mg) is dissolved inTHF, and 2-(aminomethyl)pyridine (0.25 mmol, 26 μl) and Et₃N (0.3 mmol,42 μl) are added to the solution. The reaction mixture is heated at 60°C. for overnight. After purification by preparative HPLC,2-({[(pyridin-2-ylmethyl)amino]carbonyl}amino)phenyl4-(trifluoromethyl)benzenesulfonate is obtained in 45% yield. ¹H NMR(400 MHz, MeOD-d6) 8.54 (d, 1H), 8.01(d, 2H), 7.82(m, 4H), 7.42(d, 1H),7.34(t, 1H), 7.26(m, 4H), 7.05(t, 1H), 4.41(s, 2H). ESI+ forC₂₀H₁₆F₃N₃O₄S m/z=452, (M+H)+.

Example 10 According to Scheme 102-{(E)-[2-phenylsulfonyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate [PHA-643115]

Benzenesulfonohydrazide is prepared from benzenesulfonyl chloride (500mg, 2.83 mmol) and hydrazine monohydrate (0.42 mL, 8.49 mmol) accordingto the experimental provided in Tetrahedron 2002, 58, 5513. The productis recrystallized from EtOAc/Hexane. The yield is 136 mg ofbenzenesulfonohydrazide, 28%.

Into a glass vial are placed benzenesulfonohydrazide (78 mg, 0.455mmol), 2-formylphenyl 4-(trifluoromethyl)benzenesulfonate (100 mg, 0.303mmol), and ethanol (5 mL). The resulting mixture is shaken at rt for 16h. The solution is concentrated and the crude product is dissolved inCH₂Cl₂ (20 mL). To the solution is added polystyrene-benzaldehyde (3.92g, 4.55 meq.) and the solution is shaken at 40° C. for 3 h. The solutionis filtered and concentrated. The yield is 60 mg of2-{(E)-[2-(phenylsulfonyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate, 41%. ¹H NMR (400 MHz, DMSO-d₆): □11.76 (s, 1H), 8.10–8.08 (m, 2H), 8.05–8.03 (m, 2H), 7.90 (S, 1H),7.87–7.85 (m, 2H), 7.72–7.59 (m, 4H), 7.47–7.43 (m, 1H), 7.40–7.36 (m,1H), 7.10–7.07 (m, 1H). HRMS for C₂₀H₁₅F₃N₂O₅S₂ m/z 485.0467, (M+H)+.

Table II lists the method of preparation based on the above examples andthe corresponding proton NMR and mass spectra of the compounds of theinvention.

TABLE II Compound Method ¹H NMR LRMS HRMS Ion 1. 1 (DMSO) d 11.64(2s,1H), 8.50(d, 2H), 464 (M + H)⁺ 8.01(m, 6H), 7.32(m, 5H), 3.78(2s, 2H) 2.1 (DMSO) d 11.40(2s, 1H), 7.45(m, 6H), 477 (M + H)⁺ 6.84(m, 8H), 2.40(m,4H) 3. 1 (DMSO) d 11.46(2s, 1H), 10.92(2s, 1H), 502 (M + H)⁺ 8.03(m,6H), 7.27(m, 8H), 3.80(2s, 2H) 4. 1 (DMSO) d 11.58(2s, 1H), 8.01(m, 6H),469 (M + H)⁺ 7.24(m, 6H), 3.93(2s, 2H) 5. 1 (DMSO) d 11.94(s, 1H),11.48(2s, 1H), 453 (M + H)⁺ 8.02(m, 6H), 7.21(m, 5H), 3.64(2s, 2H) 6. 1(DMSO) d 11.64(2s, 1H), 8.50(d, 2H), 464 (M + H)+ 8.01(m, 6H), 7.32(m,5H), 3.78(2s, 2H) 7. 1 (DMSO) d 11.55(2s, 1H), 7.99(m, 6H), 498 (M + H)+7.32(m, 7H), 3.71(2s, 2H) 8. 1 (DMSO) d 11.53(2s, 1H), 7.99(m, 6H), 481(M + H)+ 7.31(m, 7H), 3.72(2s, 2H) 9. 1 (DMSO) d 11.57(2s, 1H), 7.99(m,6H), 515 (M + H)+ 7.33(m, 6H), 3.74(2s, 2H) 10. 1 (DMSO) d 11.63(2s,1H), 8.02(m, 6H), 515 (M + H)+ 7.32(m, 6H), 3.87(2s, 2H) 11. 1 (DMSO) d11.43(2s, 1H), 8.00(m, 6H), 506 (M + H)+ 7.45(m, 2H), 7.12(m, 3H),6.68(m, 2H), 3.65(2s, 2H), 2.85(s, 3H), 2.83(s, 3H) 12. 1 (DMSO) d11.77(2s, 1H), 7.99(m, 6H), 551 (M − H)− 7.49(m, 2H), 7.21(m, 1H),3.91(2s, 2H) 13. 1 (DMSO) d 11.59(2s, 1H), 7.99(m, 6H), 547 (M − H)−7.68(m, 2H), 7.47(m, 3H), 7.19(m, 1H), 3.84(2s, 2H) 14. 1 (DMSO) d11.64(2s, 1H), 7.95(m, 7H), 547 (M − H)− 7.42(m, 4H), 7.18(m, 1H),3.88(2s, 2H) 15. 1 (DMSO) d 11.50(2s, 1H), 8.04(m, 6H), 551 (M − H)−7.46(m, 2H), 7.16(m, 1H), 6.85(m, 2H), 3.63(m, 11H) 16. 1 (DMSO) d11.65(2s, 1H), 8.00(m, 6H), 515 (M − H)− 7.47(m, 2H), 7.24(m, 3H),3.84(2s, 2H) 17. 1 (DMSO) d 11.63(2s, 1H), 8.01(m, 6H), 515 (M − H)−7.51(m, 4H), 7.17(m, 1H), 3.78(2s, 2H) 18. 1 (DMSO) d 11.60(2s, 1H),8.00(m, 6H), 515 (M − H)− 7.47(m, 4H), 7.21(m, 1H), 3.77(2s, 2H) 19. 1(DMSO) d 11.61(2s, 1H), 8.09(m, 6H), 561 (M − H)− 7.57(m, 6H), 7.17(m,1H), 3.81(2s, 2H) 20. 1 (DMSO) d 11.67(2s, 1H), 8.01(m, 6H), 515 (M −H)− 7.47(m, 3H), 7.16(m, 2H), 3.87(2s, 2H) 21. 1 (DMSO) d 11.58(2s, 1H),8.00(m, 6H), 545 (M − H)− 7.33(m, 7H), 3.80(2s, 2H) 22. 1 (DMSO) d11.28(2s, 1H), 8.65(m, 6H), 567 (M + H)+ 7.97(m, 4H), 7.64(m, 1H),4.78(2s, 2H) 23. 1 (DMSO) d 11.19(2s, 1H), 8.64(m, 6H), 547 (M − H)−7.81(m, 6H), 4.47(2s, 2H) 24. 1 (DMSO) d 11.03(2s, 1H), 8.65(m, 6H), 521(M − H)− 7.61(m, 6H), 4.28(m, 8H) 25. 1 (DMSO) d 11.20(2s, 1H), 8.65(m,6H), 561 (M − H)− 7.93(m, 7H), 4.67(2s, 2H) 26. 1 (DMSO) d 11.52(2s,1H), 8.01(m, 6H), 507 (M − H)− 7.46(m, 2H), 7.19(m, 5H), 3.67(2s, 2H),2.46(2s, 3H) 27. 1 (DMSO) d 11.70(2s, 1H), 7.99(m, 6H), 515 (M − H)−7.47(m, 3H), 7.19(m, 2H), 3.85(2s, 2H) 28. 1 (DMSO) d 11.66(2s, 1H),7.99(m, 6H), 497 (M − H)− 7.30(m, 6H), 3.79(2s, 2H) 29. 1 (DMSO) d11.62(2s, 1H), 8.13(m, 8H), 462 (M − H)− 7.30(m, 5H), 3.90(2s, 2H) 30. 1(DMSO) d 11.38(2s, 1H), 8.08(m, 9H), 476 (M − H)− 7.30(m, 4H), 2.91(2s,2H) 31. 1 (DMSO) d 11.63(2s, 1H), 8.01(m, 6H), 497 (M − H)− 7.33(m, 6H),3.76(2s, 2H) 32. 1 (DMSO) d 11.70(2s, 1H), 8.02(m, 9H), 597 (M − H)−7.34(m, 3H), 4.12(2s, 2H) 33. 1 (DMSO) d 11.68(2s, 1H), 7.99(m, 6H), 547(M − H)− 7.39(m, 6H), 4.00(2s, 2H) 34. 1 (DMSO) d 11.61(2s, 1H), 7.66(m,13H), 529 (M − H)− 3.84(2s, 2H) 35. 1 (DMSO) d 11.59(2s, 1H), 8.00(m,6H), 529 (M − H)− 7.42(m, 7H), 3.86(2s, 2H) 36. 1 (DMSO) d 11.48(2s,1H), 8.03(m, 6H), 491 (M − H)− 7.18(m, 7H), 3.80(m, 5H) 37. 1 (DMSO) d11.48(2s, 1H), 7.48(m, 12H), 521 (M − H)− 3.76(m, 8H) 38. 1 (DMSO) d11.58(2s, 1H), 8.00(m, 6H), 530 (M − H)− 7.37(m, 6H), 3.76(2s, 2H) 39. 1(DMSO) d 11.65(2s, 1H), 7.99(m, 9H), 597 (M − H)− 7.54(m, 3H), 4.02(2s,2H) 40. 1 (DMSO) d 11.65(2s, 1H), 8.05(m, 6H), 540 (M − H)− 7.38(m, 7H),3.91(2s, 2H) 41. 1 (DMSO) d 11.60(2s, 1H), 8.02(m, 6H), 479 (M − H)−7.32(m, 7H), 3.78(2s, 2H) 42. 1 (DMSO) d 11.54(2s, 1H), 8.03(m, 6H), 475(M − H)− 7.31(m, 7H), 3.74(2s, 2H), 2.26(2s, 3H) 43. 1 (DMSO) d11.48(2s, 1H), 8.01(m, 6H), 505 (M − H)− 7.12(m, 6H), 5.99(2s, 2H),3.62(2s, 2H) 44. 1 (DMSO) d 11.48(2s, 1H), 8.01(m, 6H), 491 (M − H)−7.19(m, 7H), 3.78(2s, 2H) 45. 1 (DMSO) d 11.28(2s, 1H), 7.95(m, 6H), 467(M − H)− 7.32(m, 3H), 2.23(m, 2H), 1.32(m, 10H) 46. 1 (DMSO) d 11.30(2s,1H), 7.88(m, 6H), 489 (M − H)− 7.32(m, 8H), 2.62(m, 2H), 2.54(m, 2H),1.85(m, 2H) 47. 1 (DMSO) d 11.28(2s, 1H), 7.93(m, 6H), 503 (M − H)−7.31(m, 8H), 2.62(m, 2H), 2.52(m, 2H), 1.60(m, 4H) 48. 1 (DMSO) d11.56(2s, 1H), 8.09(m, 4H), 481 (M + H)⁺ 7.49(m, 9H), 3.75(2s, 2H) 49. 1(DMSO) d 11.48(2s, 1H), 10.77(2s, 1H), 530 (M − H)− 8.05(m, 6H), 7.26(m,6H), 6.73(m, 1H), 3.77(2s, 2H), 3.70(2s, 3H) 50. 1 (DMSO) d 11.50(2s,1H), 8.02(m, 6H), 521 (M − H)− 7.31(m, 3H), 6.46(m, 3H), 3.72(m, 6H) 51.1 (DMSO) d 11.42(2s, 1H), 8.03(m, 6H), 521 (M − H)− 7.26(m, 3H), 6.51(m,2H), 3.60(m, 8H) 52. 1 (DMSO) d 11.56(2s, 1H), 8.01(m, 6H), 540 (M − H)−7.48(m, 4H), 7.20(m, 3H), 3.71(2s, 2H) 53. 1 (DMSO) d 11.63(d, 1H),8.10(m, 6H), 507 (M − H)− 7.33(m, 4H), 6.56(m, 3H), 3.71(2s, 2H) 54. 1(DMSO) d 11.41(2s, 1H), 7.62(m, 10H), 465 (M − H)− 6.23(m, 2H), 2.88(m,4H) 55. 1 (DMSO) d 11.51(2s, 1H), 8.02(m, 6H), 551 (M − H)− 6.99(m, 5H),3.65(m, 11H) 56. 1 (DMSO) d 11.53(2s, 1H), 7.54(m, 18H), 567 (M − H)−5.11(d, 2H), 3.76(2s, 2H) 57. 1 (DMSO) d 11.51(2s, 1H), 7.51(m, 18H),553 (M − H)− 3.77(2s, 2H) 58. 1 (DMSO) d 11.36(2s, 1H), 7.94(m, 6H), 505(M − H)− 7.12(m, 7H), 3.73(2s, 3H), 2.81(m, 4H) 59. 1 (DMSO) d 11.66(2s,1H), 8.02(m, 6H), 493 (M − H)− 7.30(m, 8H), 3.77(2s, 2H) 60. 1 (DMSO) d11.55(2s, 1H), 8.01(m, 6H), 587 (M − H)− 7.39(m, 7H), 3.68(m, 2H) 61. 1(DMSO) d 11.64(2s, 1H), 8.24(m, 9H), 542 (M − H)− 7.33(m, 3H), 3.83(2s,2H) 62. 1 (DMSO) d 11.57(2s, 1H), 8.01(m, 6H), 541 (M − H)− 7.33(m, 7H),3.74(2s, 2H) 63. 1 (DMSO) d 11.62(2s, 1H), 8.05(m, 8H), 498 (M − H)−7.32(m, 4H), 3.81(2s, 2H) 64. 1 (DMSO) d 11.63(2s, 1H), 8.10(m, 6H), 477(M − H)− 7.21(m, 8H), 4.85(2s, 2H) 65. 1 (DMSO) d 11.61(2s, 1H), 8.04(m,7H), 501 (M − H)− 7.26(m, 7H), 4.00(m, 2H), 3.98(2s, 2H) 66. 1 (DMSO) d11.63(2s, 1H), 8.02(m, 6H), 551 (M − H)− 7.30(m, 3H), 6.24(d, 2H),3.61(2s, 2H) 67. 1 (DMSO) d 11.47(2s, 1H), 8.01(m, 6H), 505 (M − H)−7.18(m, 7H), 4.00(m, 2H), 3.62(2s, 2H), 1.31(m, 3H) 68. 1 (DMSO) d11.60(2s, 1H), 8.01(m, 10H), 511 (M − H)− 7.47(m, 5H), 7.17(m, 1H),3.90(2s, 2H) 69. 1 (DMSO) d 11.64(2s, 1H), 8.02(m, 8H), 539 (M − H)−7.35(m, 5H), 3.87(2s, 2H), 3.21(2s, 3H) 70. 1 (DMSO) d 11.52(2s, 1H),8.04(m, 6H), 569 (M − H)− 7.23(m, 6H), 3.71(2s, 2H), 3.77(2s, 3H) 71. 2DMSO: 12.07(s, 1H), 8.34(s, 1H), 8.22–8.20(m, 499.0942 (M + H)+ 1H),8.14–8.12(m, 1H), 8.09–7.99(m, 6H), 7.75–7.74(m, 1H), 7.67–7.47(m, 5H),7.21–7.19(m, 1H) 72. 2 DMSO: 12.15–12.07(m, 1H), 8.29(s, 517.0003 M+0.6H), 8.10(m, 0.4H), 8.08–8.03(m, 4H), 7.97–7.95(m, 0.5H), 7.70(m,0.5H), 7.64(m, 1H), 7.57–7.42(m, 3H), 7.34–7.28(m, 1H), 7.17–7.14(m, 1H)73. 2 DMSO: 12.02–12.00(m, 1H), 8.29(s, 483.0382 (M + H)+ 0.6H),8.09–8.03(m, 4H), 8.00(s, 0.4H), 7.97–7.94(m, 0.6H), 7.62–7.36(m, 5.7H),7.29–7.28(m, 0.7H), 7.18–7.15(m, 1H) 74. 2 DMSO: 12.10–12.03(m, 1H),8.29(s, 516.9994 (M − H)− 0.5H), 8.09–8.04(m, 4H), 8.02(s, 0.5H),7.97–7.94(m, 0.5H), 7.82–7.81(m, 0.5H), 7.73–7.72(m, 0.5H), 7.61(m, 1H),7.54–7.50(m, 1H), 7.49–7.41(m, 1.5H), 7.33–7.32(m, 1H), 7.17–7.14(m, 1H)75. 2 DMSO: 11.31–11.24(m, 1H), 8.06–8.00(m, 479.0879 (M + H)+ 4H),7.91(s, 1H), 7.80–7.78(m, 1H), 7.50–7.45(m, 1H), 7.43–7.35(m, 6H),7.21–7.19(m, 1H), 5.17(s, 2H) 76. 2 DMSO: 12.01(s, 1H), 9.06–9.05(m,1H), 450.0728 8.80–8.79(m, 1H), 8.38(s, 1H), 8.26–8.23(m, 1H),8.08–8.03(m, 4H), 7.94–7.91(m, 1H), 7.62–7.59(m, 1H), 7.55–7.51(m, 1H),7.49–7.45(m, 1H), 7.20–7.18(m, 1H) 77. 2 DMSO: 12.17–12.12(m, 1H),8.31 - (m, 494.0635 (M + H)+ 0.3H), 8.19–8.15(m, 1H), 8.11–8.03(m, 4H),7.98–7.86(m, 2H), 7.84–7.73(m, 1.5H), 7.61–7.59(m, 0.7H), 7.54–7.41(m,1.5H), 7.32–7.29(0.5H), 7.23–7.21(m, 0.5H), 715–7.11(m, 1H) 78. 2 DMSO:11.68(m, 1H), 8.10–8.08(m, 499.06 (M + H)+ 2H), 8.05–8.03(m, 2H),7.89(s, 1H), 7.75–7.70(m, 2H), 7.47–7.36(m, 4H), 7.10–7.08(m, 1H),2.36(s, 3H) 79. 2 DMSO: 11.56(s, 1H), 8.38(m, 1H), 8.10–8.08(m, 492.1187(M + H)+ 2H), 8.03–8.01(m, 2H), 7.90–7.89(m, 1H), 7.81–7.79(m, 2H),7.50–7.42(m, 2H), 7.17–7.15(m, 1H), 6.78–6.76(m, 2H), 3.02(m, 6H) 80. 2(DMSO) 11.27(d, 1H), 8.04(m, 4.5), 7.82(m, 481.0 (M + H)+ 1.5), 7.45(m,2H), 7.17(s, 1H), 2.40–1.78(m, 5H), 1.54–1.00(m, 8H) 81. 2 (DMSO)10.46(d, 1H), 7.97(m, 4H), 511.0696 (M + H)+ 7.53–7.13(m, 8H), 3.77(m,2H), 2.02(m, 3H) 82. 2 DMSO: 11.98–11.89(m, 1H), 9.29–9.26(m, 533.0848(M + H)+ 1H), 8.89–8.88(m, 2H), 8.21(s, 0.2H), 8.08–8.07(m, 4H), 7.95(s,0.8H), 7.89–7.82(m, 1H), 7.53–7.35(m, 2H), 7.18–7.11(m, 1H),4.54–4.25(m, 2H) 83. 2 DMSO: 12.03–12.00(m, 1H), 8.63–8.53(m, 496.0587(M + H)+ 1H), 8.35(s, 0.7H), 8.10–8.05(m, 4H), 8.03(s, 0.3H),7.96–7.94(m, 0.7H), 7.90–7.89(m, 0.7H), 7.64–7.20(m, 3.6H), 7.15–7.13(m,1H), 2.49(s, 3H) 84. 2 (DMSO) 11.27(d, 1H), 8.04(m, 4.5H), 455.1239 (M +H)+ 7.87–7.72(m, 1.5H), 7.54–7.38(m, 2H), 7.29–7.07(m, 1H), 2.18(m, 2H),1.74(m, 2H), 1.55(m, 4H), 1.15(m, 2H) 85. 2 DMSO: 11.69–11.58(m, 1H),8.32(s, 493.1048 (M + H)+ 0.8H), 8.13–8.03(m, 4H), 8.00(s, 0.2H),7.96–7.94(m, 0.8H), 7.58–7.55(m, 0.8H), 7.52–7.43(m, 2.4H), 7.42–7.38(m,0.5H), 7.33–7.26(m, 0.5H), 7.22–7.12(m, 2H), 7.08–6.95(m, 1H),4.18–3.96(m, 2H), 1.39–1.05(m, 3H) 86. 2 DMSO: 11.60–11.59(m, 1H),8.36(s, 522.0 (M + H)+ 0.4H), 8.09–7.85(m, 5.6H), 7.51–7.47(m, 1H),7.44–7.41(m, 1H), 7.20–7.03(m, 2H), 6.39–6.30(m, 2H), 6.23–6.17(m, 1H),4.97–4.60(m, 2H), 2.90(s, 3H), 2.86(s, 3H) 87. 2 DMSO: 11.70–11.51(m,1H), 8.27(s, 478.9 (M + H)+ 0.8H), 8.10–8.01(m, 4H), 7.96(s, 0.2H),7.92–7.90(m, 0.8H), 7.57–7.28(m, 4H), 7.21–7.18(m, 1.8H), 7.14–7.12(m,0.2H), 7.09–7.06(m, 1H), 7.01–6.97(m, 0.2H), 3.91–3.70(m, 3H) 88. 2DMSO: 12.02–11.99(m, 1H), 8.30(m, 526.8/ (M + H)+ 0.6H), 8.10–8.04(m,4H), 8.02(m, 528.8 0.4H), 7.97–7.95(m, 0.6H), 7.76–7.66(m, 1H),7.54–7.29(m, 5.4H), 7.17–7.13(m, 1H) 89. 2 DMSO: 12.34–12.23(m, 1H),9.03–8.93(m, 517.9 (M + H)+ 1.5H), 8.76(s, 0.5H), 8.28(s, 0.5H),8.08–8.03(m, 4.5H), 7.98–7.94(m, 1H), 7.89–7.87(m, 0.5H), 7.56–7.52(m,0.5H), 7.49–7.42(m, 1H), 7.29–7.25(m, 0.5H), 7.19–7.17(m, 1.5H) 90. 2DMSO: 11.96–11.88(m, 1H), 8.28(s, 466.9 (M + H)+ 0.7H), 8.07–8.02(m,4H), 7.96(s, 0.3H), 7.93–7.91(m, 0.6H), 7.67–7.60(m, 1.4H), 7.56–7.26(m,5H), 7.20–7.18(m, 1H) 91. 2 DMSO: 11.55–11.49(m, 1H), 8.10(m, 546.1325(M + H)+ 0.3H), 8.06–8.00(m, 4H), 7.87(s, 0.7H), 7.85–7.79(m, 1H),7.51–7.46(m, 1H), 7.44–7.33(m, 3H), 7.30–7.10(m, 4H), 4.44–4.35(m, 2H),3.88–3.80(m, 0.7H), 3.54–3.46(m, 1H), 3.32–3.28(m, 1H), 3.32–3.15(m,0.3H), 2.65–2.54(m, 2H) 92. 2 DMSO: 11.98–11.93(m, 1H), 8.60–8.48(m,464.0882 (M + H)+ 1H), 8.28(s, 0.7H), 8.08–8.04(m, 4.3H), 8.00(s, 0.3H),7.96–7.94(m, 0.7H), 7.86–7.83(m, 0.6H), 7.67–7.63(m, 0.4H), 7.55–7.50(m,0.5H), 7.48–7.45(m, 1H), 7.40–7.37(m, 0.5H), 7.33–7.24(m, 1H),7.20–7.17(m, 1H), 2.56–2.35(m, 3H) 93. 2 DMSO: 12.07(s, 1H),8.57–8.56(m, 1H), 464.0882 (M + H)+ 8.49(s, 1H), 8.11–8.09(m, 2H),8.03–8.01(m, 2H), 7.93–7.91(m, 1H), 7.84–7.82(m, 1H), 7.56–7.43(m, 3H),7.21–7.19(m, 1H), 2.55(s, 3H) 94. 2 (DMSO) 11.25(m, 1H), 8.02(m, 4.5H),521 (M + H)+ 7.82(m, 1.5H), 7.46(m, 2H), 7.19(m, 1H), 2.34–1.82(m, 6H),1.73–1.49(m, 10H) 95. 2 (DMSO) 11.36(d, 1H), 8.14–8.00(m, 456.9 (M + H)+4.5H), 7.84(m, 1.5H), 7.42(m, 2H), 7.17(m, 1H), 4.16(m, 1H), 3.75(m,1H), 3.59(m, 1H), 2.92–2.53(m, 1H), 2.36(m, 1H), 1.99(m, 1H), 1.83(m,1H), 1.52(m, 1H) 96. 2 1H NMR(DMSO) d 11.33(s, 1H) 8.36(m, 598 (M + H)+2H) 8.08(m, 1H) 7.95(m, 2H) 7.78(m, 1H) 7.52(m, 1H) 7.26(m, 1H) 7.19(m,1H), 7.15(m, 2H), 7.10(m, 1H) 7.03(m, 1H) 6.82(m, 1H), 6.77(m, 1H)6.70(m, 2H) 5.1(m, 1H) 4.15(d, 2H) 3.71(m, 5H) 97. 2 1H NMR(DMSO) d11.44(s, 1H) 8.07(m, 528 (M + H)+ 6H) 7.24(m, 9H) 6.26(m, 2H) 4.05(s,2H) 98. 2 1H NMR(DMSO) d 11.33(s, 1H), 8.02(m, 532 (M + H)+ 6H), 7.45(m,2H) 7.14(m, 2H) 6.47(m, 3H) 3.79(s, 2H) 3.16(m, 4H) 1.92(m, 4H) 99. 2 1HNMR(DMSO) d 11.33(s, 1H) 9.85(s, 625 (M + H)+ 1H) 8.36(m, 2H) 8.08(m,1H) 7.95(m, 2H) 7.78(m, 1H) 7.51(m, 1H) 7.31(m, 2H) 7.29(m, 2H), 7.25(m,1H) 7.15(m, 3H) 6.82(m, 1H) 6.7(m, 1H) 6.13(bs, 1H) 4.15(d, 2H), 3.75(s,2H) 2.18(s, 3H) 100. 2 DMSO: 11.80(s, 1H), 8.27(s, 1H), 8.08–8.03(m,463.0943 (M + H)+ 4H), 7.97–7.93(m, 1H), 7.53–7.41(m, 3H), 7.34–7.19(m,4H), 2.37(s, 3H) 101. 2 DMSO: 11.29(s, 0.5H), 11.07(s, 0.5H), 455.123(M + H)+ 8.09(s, 0.5H), 8.07–7.99(m, 4H), 7.84–7.82(m, 1H), 7.78–7.76(m,0.5H), 7.51–7.40(m, 2H), 7.26–7.13(m, 1H), 3.00–2.91(m, 0.5H),2.20–2.12(m, 0.5 H), 1.79–1.61(m, 5H), 1.44–1.15(m, 5 H) 102. 2 DMSO:12.24–12.20(m, 1H), 8.23(s, 485.0577 (M + H)+ 0.5H), 8.07–8.01(m, 4.5H),7.95–7.92(m, 0.5H), 7.68–7.52(m, 1.5H), 7.49–7.43(m, 1H), 7.33–7.27(m,2H), 7.22–7.17(m, 2H) 103. 2 DMSO: 12.32–12.24(m, 1H), 8.23(s, 534.8(M + H)+ 0.4H), 8.08–8.00(m, 4.6H), 7.97–7.95(m, 0.4H), 7.84–7.65(m,3H), 7.56–7.52(m, 0.4H), 7.49–7.41(m, 1H), 7.29–7.25(m, 0.6H),7.21–7.16(m, 1.6H) 104. 2 DMSO: 12.08–12.04(m, 1H), 8.28(m, 516.9 (M +H)+ 0.5H), 8.08–8.02(m, 4H), 7.99(s, 0.5 H), 7.97–7.94(m, 0.5H),7.90–7.88(m, 0.5H), 7.85–7.72(m, 2H), 7.69–7.65(m, 1H), 7.55–7.51(m,0.5H), 7.49–7.39(m, 1.5H), 7.27–7.24(m, 0.5H), 7.20–7.16(m, 1.5H) 105. 2DMSO: 11.70(s, 1H), 8.10–8.08(m, 2 512.9 (M + H)+ H), 8.06–8.04(m, 2H),7.89(s, 1H), 7.77–7.75(m, 2H), 7.73–7.71(m, 1H), 7.47–7.43(m, 3H),7.40–7.37(m, 1H), 7.10–7.07(m, 1H), 2.7–2.64(m, 2H), 1.19–1.15(m, 3H)106. 2 (DMSO) d 11.45(2s, 1H), 8.01(m, 6H), 465 (M − H)− 7.20(m, 5H),3.56(2s, 2H), 3.61(m, 3H) 107. 2 (DMSO) d 12.03(2s, 1H), 8.06(m, 6H),599 (M − H)− 7.32(m, 3H), 5.01(2s, 2H) 108. 3 (DMSO) d 11.67–11.44(2s,1H), 8.22–7.99(2s, 393 (M − H)⁻ 1H), 7.47(m, 13H), 3.91–3.54(2s, 2H).109. 3 (DMSO) d 11.71–11.45(2s, 1H), 8.13(m, 399 (M − H)⁻ 2H), 7.88(m,2H), 7.35(m, 9H), 3.94–3.54(2s, 2H). 110. 3 (DMSO) d 11.79–11.54(2s,1H), 8.37–8.13(2s, 407 (M − H)⁻ 1H), 7.93(m, 1H), 7.73(m, 2H), 7.33(m,9H), 6.78(m, 1H), 3.95–3.55(2s, 2H), 2.65(s, 3H). 111. 3 (DMSO) d11.69–11.40(2s, 1H), 8.25–7.99(2s, 407 (M − H)⁻ 1H), 7.84(m, 1H),7.72(s, 1H), 7.32(m, 11H), 3.90–3.54(2s, 2H), 2.35(s, 3H). 112. 3 (DMSO)d 11.80–11.54(2s, 1H), 8.34–8.11(2s, 411 (M − H)⁻ 1H), 7.88(m, 3H),7.40(m, 9H), 7.03(m, 1H), 3.94–3.55(2s, 2H). 113. 3 (DMSO) d11.70–11.47(2s, 1H), 8.25–8.00(2s, 411 (M − H)⁻ 1H), 7.88(m, 1H),7.40(m, 12H), 3.92–3.54(2s, 2H). 114. 3 (DMSO) d 11.68–11.46(2s, 1H),8.07(m, 418 (M − H)⁻ 6H), 7.31(m, 8H), 3.92–3.56(2s, 2H). 115. 3 (DMSO)d 11.67–11.45(2s, 1H), 8.01(m, 418 (M − H)⁻ 6H), 7.29(m, 8H),3.93–3.56(2s, 2H). 116. 3 (DMSO) d 11.70–11.45(2s, 1H), 8.26–8.02(2s,427 (M − H)⁻ 1H), 7.83(m, 4H), 7.38(m, 9H), 3.92–3.54(2s, 2H). 117. 3(DMSO) d 11.70–11.45(2s, 1H), 8.26–8.02(2s, 427 (M − H)⁻ 1H), 7.83(m,4H), 7.38(m, 9H), 3.92–3.54(2s, 2H). 118. 3 (DMSO) d 11.71–11.48(2s,1H), 8.12(m, 429 (M − H)⁻ 2H), 7.88(m, 1H), 7.72(m, 2H), 7.32(m, 8H),3.93–3.54(2s, 2H). 119. 3 (DMSO) d 11.63–11.35(2s, 1H), 8.58(m, 443 (M −H)⁻ 1H), 7.68(m, 16H), 3.74–3.49(2s, 2H). 120. 3 (DMSO) d11.69–11.44(2s, 1H), 8.13(m, 445 (M − H)⁻ 2H), 7.84(m, 2H), 7.66(m, 1H),7.34(m, 8H), 3.92–3.54(2s, 2H). 121. 3 (DMSO) d 11.64–11.37(2s, 1H),7.99(m, 449 (M − H)⁻ 2H), 7.69(m, 4H), 7.30(m, 8H), 3.86–3.53(2s, 2H),1.26–1.23(2s, 9H). 122. 3 (DMSO) d 11.67–11.37(2s, 1H), 8.11(m, 461 (M −H)⁻ 4H), 7.86(m, 2H), 7.33(m, 8H), 3.89–3.52(2s, 2H). 123. 3 (DMSO) d11.65–11.40(2s, 1H), 8.01(m, 461 (M − H)⁻ 6H), 7.32(m, 8H),3.88–3.53(2s, 2H). 124. 3 (DMSO) d 11.85–11.59(2s, 1H), 8.42–8.19(2s,461 (M − H)⁻ 1H), 8.10(m, 1H), 7.97(m, 2H), 7.70(m, 1H), 7.34(m, 7H),6.96(m, 1H), 3.97–3.56(2s, 2H). 125. 3 (DMSO) d 11.68–11.42(2s, 1H),8.11(m, 461 (M − H)⁻ 2H), 7.88(m, 2H), 7.73(m, 1H), 7.36(m, 8H),3.92–3.55(2s, 2H). 126. 3 (DMSO) d 11.73–11.45(2s, 1H), 8.17(m, 461 (M −H)⁻ 2H), 7.88(m, 3H), 7.38(m, 8H), 3.93–3.55(2s, 2H). 127. 3 (DMSO) d11.70–11.43(2s, 1H), 8.01(m, 471 (M − H)⁻ 5H), 7.37(m, 9H),3.92–3.55(2s, 2H). 128. 3 (DMSO) d 11.66–11.42(2s, 1H), 8.19–7.93(2s,471 (M − H)⁻ 1H), 7.82(m, 5H), 7.29(m, 8H), 3.93–3.55(2s, 2H). 129. 3(DMSO) d 11.67–11.44(2s, 1H), 8.01(m, 411 (M − H)⁻ 4H), 7.32(m, 10H),3.92–3.55(2s, 2H). 130. 3 (DMSO) d 11.79–11.50(2s, 1H), 8.38–8.12(2s,421 (M − H)⁻ 1H), 7.93(m, 1H), 7.63(m, 1H), 7.36(m, 9H), 6.82(m, 1H),3.93–3.55(2s, 2H), 2.56–2.52(2s, 3H), 2.31(s, 3H). 131. 3 (DMSO) d11.66–11.40(2s, 1H), 8.21–7.95(2s, 423 (M − H)⁻ 1H), 7.81(m, 3H),7.26(m, 10H), 3.90–3.81(2s, 3H), 3.77–3.54(2s, 2H). 132. 3 (DMSO) d11.85–11.59(2s, 1H), 8.45–8.24(2s, 427 (M − H)⁻ 1H), 7.79(m, 5H),7.32(m, 7H), 6.89(m, 1H), 3.97–3.56(2s, 2H). 133. 3 (DMSO) d11.80–11.54(2s, 1H), 8.33–8.08(2s, 429 (M − H)⁻ 1H), 7.92(m, 2H),7.69(m, 1H), 7.34(m, 8H), 7.07(m, 1H), 3.95–3.55(2s, 2H). 134. 3 (DMSO)d 11.61–11.38(2s, 1H), 7.92(m, 435 (M − H)⁻ 4H), 7.28(m, 10H),3.89–3.53(2s, 2H), 2.56(m, 2H), 1.53(m, 2H), 0.83(m, 3H). 135. 3 (DMSO)d 11.61–11.38(2s, 1H), 7.93(m, 435 (M − H)⁻ 4H), 7.31(m, 10H),3.89–3.52(2s, 2H), 2.92(m, 1H), 1.18–1.12(2d, 6H). 136. 3 (DMSO) d11.74–11.44(2s, 1H), 8.64(m, 443 (M − H)⁻ 1H), 8.30(m, 4H), 7.79(m, 4H),7.30(m, 7H), 6.63(m, 1H), 3.91–3.55(2s, 2H). 137. 3 (DMSO) d11.85–11.60(2s, 1H), 8.44–8.21(2s, 445 (M − H)⁻ 1H), 7.99(m, 3H),7.37(m, 8H), 6.93(m, 1H), 3.97–3.56(2s, 2H). 138. 3 (DMSO) d11.81–11.52(2s, 1H), 8.42–8.17(2s, 453 (M − H)⁻ 1H), 7.93(m, 1H),7.31(m, 10H), 7.08(m, 1H), 3.76(m, 8H). 139. 3 (DMSO) d 11.84–11.60(2s,1H), 8.44–8.22(2s, 461 (M − H)⁻ 1H), 7.95(m, 4H), 7.34(m, 7H), 7.00(m,1H), 3.96–3.56(2s, 2H). 140. 3 (DMSO) d 11.86–11.60(2s, 1H),8.44–8.28(2s, 471 (M − H)⁻ 1H), 8.00(m, 3H), 7.70(m, 2H), 7.33(m, 7H),6.85(m, 1H), 3.98–3.56(2s, 2H). 141. 3 (DMSO) d 11.81–11.54(2s, 1H),8.37–8.13(2s, 477 (M − H)⁻ 1H), 7.95(m, 3H), 7.68(m, 2H), 7.33(m, 7H),6.85(m, 1H), 3.98–3.56(2s, 2H). 142. 3 (DMSO) d 11.65–11.42(2s, 1H),8.02(m, 477 (M − H)⁻ 4H), 7.60(m, 2H), 7.30(m, 8H), 3.90–3.53(2s, 2H).143. 3 (DMSO) d 11.68–11.41(2s, 1H), 8.26–8.01(2s, 423 (M − H)⁻ 1H),7.87(m, 1H), 7.32(m, 12H), 3.73(m, 8H). 144. 3 (DMSO) d 11.67–11.43(2s,1H), 8.25–7.98(2s, 469 (M − H)⁻ 1H), 7.81(m, 7H), 7.34(m, 11H),3.81–3.49(2s, 2H). 145. 3 (DMSO) d 11.60–11.39(2s, 1H), 7.98(m, 437 (M −H)⁻ 2H), 7.70(m, 2H), 7.42(m, 4H), 7.22(m, 2H), 6.86(m, 3H), 3.70(m,5H), 2.34–2.29(2s, 3H). 146. 3 (DMSO) d 11.62–11.40(2s, 1H), 8.01(m, 491(M − H)⁻ 6H), 7.45(m, 2H), 7.19(m, 2H), 6.84(m, 3H), 3.68(m, 5H). 147. 3(DMSO) d 11.64–11.46(2s, 1H), 7.98(m, 441 (M − H)⁻ 2H), 7.71(m, 2H),7.28(m, 8H), 7.12(m, 1H), 3.95–3.58(2s, 2H), 2.35–2.30(2s, 3H). 148. 3(DMSO) d 11.66–11.46(2s, 1H), 8.00(m, 495 (M − H)⁻ 6H), 7.32(m, 7H),3.92–3.56(2s, 2H). 149. 3 (DMSO) d 11.56–11.34(2s, 1H), 7.98(m, 467 (M −H)⁻ 2H), 7.74(m, 2H), 7.42(m, 4H), 7.09(m, 1H), 6.83(m, 3H), 3.64(m,8H), 3.32–3.29(2s, 3H). 150. 3 (DMSO) d 11.58–11.35(2s, 1H), 8.00(m, 521(M − H)⁻ 6H), 7.45(m, 2H), 7.15(m, 1H), 6.84(m, 3H), 3.63(m, 8H). 151. 3(DMSO) d 11.65–11.40(2s, 1H), 8.22–7.95(2s, 453 (M − H)⁻ 1H), 7.81(m,3H), 7.23(m, 6H), 6.84(m, 3H), 3.69(m, 8H). 152. 3 (DMSO) d11.62–11.35(2s, 1H), 8.25–7.97(2s, 483 (M − H)⁻ 1H), 7.84(m, 1H),7.27(m, 7H), 6.85(m, 3H), 3.68(m, 11H). 153. 3 (DMSO) d 11.79–11.51(2s,1H), 8.41–8.17(2s, 483 (M − H)⁻ 1H), 7.93(m, 1H), 7.31(m, 6H), 7.07(m,1H), 6.85(m, 3H), 3.73(m, 11H) 154. 3 (DMSO) d 11.80–11.50(2s, 1H),8.42–8.17(2s, 483 (M − H)⁻ 1H), 7.93(m, 1H), 7.64–7.61(2s, 1H), 7.02(m,9H), 3.73(m, 11H). 155. 3 473 (M + H)+ 156. 3 469 (M + H)+ 157. 3 453(M + H)+ 158. 3 457 (M + H)+ 159. 3 457 (M + H)+ 160. 3 469 (M + H)+161. 3 483 (M + H)+ 162. 3 489 (M + H)+ 163. 3 453 (M + H)+ 164. 3 461(M + H)+ 165. 3 523 (M + H)+ 166. 3 572 (M + H)+ 167. 3 527 (M + H)+168. 3 507 (M + H)+ 169. 3 602 (M + H)+ 170. 3 523 (M + H)+ 171. 3 507(M + H)+ 172. 3 511 (M + H)+ 173. 3 511 (M + H)+ 174. 3 527 (M + H)+175. 3 511 (M + H)+ 176. 3 515 (M + H)+ 177. 3 453 (M + H)+ 178. 3 507(M + H)+ 179. 3 511 (M + H)+ 180. 3 473 (M + H)+ 181. 3 (MeOD-d6)8.57(d, 1H), 8.42(d, 1H), 440 (M + H)+ 8.26(m, 2H), 7.85(d, 2H), 7.41(m,3H), 7.26(m, 1H), 6.88(m, 3H), 4.03(s, 1H), 3.82(s, 2H), 3.76(s, 1H),3.62(s, 1H), 2.42(d, 3H) 182. 3 (DMSO) d 11.48–11.25(2s, 1H), 8.52(m,481 (M − H)⁻ 2H), 8.13(m, 2H), 7.84(m, 1H), 7.32(m, 4H), 6.84(m, 3H),3.62(m, 5H). 183. 3 (DMSO) d 11.59–11.38(2s, 1H), 7.92(m, 493 (M − H)⁻4H), 7.29(m, 6H), 6.86(m, 3H), 3.68(m, 5H), 2.56(m, 2H), 1.52(m, 2H),1.23(m, 4H), 0.84(m, 3H). 184. 3 (DMSO) d 11.59–11.37(2s, 1H), 7.91(m,465 (M − H)⁻ 4H), 7.29(m, 6H), 6.86(m, 3H), 3.68(m, 5H), 2.57(m, 2H),1.52(m, 2H), 0.82(m, 3H). 185. 3 (MeOD-d6) 8.60(m, 1H), 7.78(m, 1H), 440(M + H)+ 7.63(m, 2H), 7.53(m, 1H), 7..32(d, 2H), 7.22(m, 2H), 6.93(m,2H), 6.81(m, 2H), 4.04(S, 1H), 3.87(S, 1H), 3.73(s, 2H), 3.59(s, 1H),2.27(S, 3H) 186. 3 (DMSO) d 11.63–11.40(2s, 1H), 8.20–7.94(2s, 481 (M −H)⁻ 1H), 7.86(m, 1H), 7.70(m, 2H), 7.42(m, 2H), 7.16(m, 4H), 6.85(m,3H), 4.67(m, 1H), 3.69(m, 5H), 1.24(m, 6H). 187. 3 (DMSO) d11.74–11.49(2s, 1H), 8.30–8.04(2s, 497 (M − H)⁻ 1H), 7.94(m, 1H),7.48(m, 3H), 7.23(m, 2H), 6.85(m, 3H), 3.72(m, 5H). 188. 3 (DMSO) d11.71–11.50(2s, 1H), 7.73(m, 503 (M − H)⁻ 12H), 6.82(m, 3H), 3.69(m,5H), 2.14–2.08(2s, 3H). 189. 3 (DMSO) d 11.82–11.52(2s, 1H),8.38–8.27(2s, 507 (M + H)⁺ 1H), 7.94(m, 4H), 7.70(m, 1H), 7.48(m, 2H),7.26(m, 2H), 6.84(m, 3H), 5.34–5.32(2s, 2H), 3.75(m, 5H). 190. 3 (DMSO)d 11.70–11.48(2s, 1H), 8.23–7.99(2s, 507 (M − H)⁻ 1H), 7.91(m, 1H),7.51(m, 4H), 7.21(m, 2H), 6.85(m, 3H), 3.72(m, 5H). 191. 3 (DMSO) d11.65–11.44(2s, 1H), 8.00(m, 515 (M − H)⁻ 4H), 7.65(m, 4H), 7.45(m, 7H),6.83(m, 3H), 3.71(m, 5H). 192. 3 (DMSO) d 11.69–11.44(2s, 1H), 8.13(m,564 (M − H)⁻ 2H), 7.89(m, 3H), 7.47(m, 2H), 7.23(m, 2H), 6.81(m, 3H),3.62(m, 5H). 193. 3 527 (M + H)⁺ 194. 3 531 (M + H)⁺ 195. 3 (DMSO) d11.65–11.41(2s, 1H), 8.01(m, 465 (M − H)⁻ 6H), 7.44(m, 2H), 7.17(m, 2H),6.84(m, 3H), 3.67(m, 5H), 2.60–2.59(2S, 3H). 196. 3 (DMSO) d11.66–11.44(2s, 1H), 8.66(m, 489 (M − H)⁻ 1H), 8.05(m, 3H), 7.89(m, 6H),7.17(m, 2H), 6.77(m, 4H), 3.63(m, 5H). 197. 3 (DMSO) d 11.63–11.39(2s,1H), 8.21(m, 490 (M − H)⁻ 8H), 7.44(m, 2H), 7.18(m, 2H), 6.82(m, 3H),3.62(m, 5H). 198. 3 (DMSO) d 11.62–11.38(2s, 1H), 7.99(m, 493 (M − H)⁻2H), 7.74(m, 2H), 7.47(m, 2H), 7.40(m, 2H), 7.18(m, 2H), 6.85(m, 3H),3.67(m, 5H), 1.57(m, 2H), 1.22–1.18(2s, 6H), 0.53(m, 3H). 199. 3 (DMSO)d 11.64–11.40(2s, 1H), 8.22–7.94(2s, 495 (M − H)⁻ 1H), 7.84(m, 1H),7.72(m, 2H), 7.42(m, 2H), 7.17(m, 4H), 6.86(m, 3H), 3.98(m, 2H), 3.69(m,5H), 1.67(m, 2H), 1.40(m, 2H), 0.92(m, 3H). 200. 3 (DMSO) d11.68–11.44(2s, 1H), 7.99(m, 496 (M − H)⁻ 8H), 7.22(m, 2H), 6.82(m, 3H),3.62(m, 5H). 201. 3 (DMSO) d 11.68–11.50(2s, 1H), 8.57(m, 516 (M − H)⁻1H), 8.04(m, 3H), 7.46(m, 4H), 7.23(m, 6H), 6.84(m, 3H), 3.72(m, 5H).202. 3 (DMSO) d 11.64–11.44(2s, 1H), 7.98(m, 533 (M − H)⁻ 4H), 7.44(m,2H), 7.19(m, 8H), 6.83(m, 3H), 3.71(m, 5H). 203. 3 (MeOD-d6) 8.24(s,1H), 8(m, 2H), 507 (M + H)+ 7.93(d, 1H), 7.81(s, 1H), 7.32(m, 3H),7.12(m, 1H), 6.99(m, 1H), 6.86(m, 2H), 3.89(S, 1H), 3.83(S, 1H), 3.76(s,2H), 3.59(s, 1H), 2.49(S, 1H), 2.46(S, 2H) 204. 3 (CDCl3) 8.56(s, 1H),7.90(d, 1H), 7.72(d, 453 (M + H)+ 3H), 7.56(d, 1H), 7.38–6.80(m, 6H),4.00(s, 1H), 3.56(s, 1H), 2.45(t, 3H) 205. 3 461 (M + H)+ 206. 3 515(M + H)+ 207. 3 511 (M + H)+ 208. 3 457 (M + H)+ 209. 3 473 (M + H)+210. 3 527 (M + H)+ 211. 3 513 (M + H)+ 212. 3 461 (M + H)+ 213. 3 498(M + H)+ 214. 3 494 (M + H)+ 215. 3 499 (M + H)+ 216. 3 (DMSO) d11.68–11.41(2s, 1H), 8.37(m, 509 (M − H)⁻ 1H), 8.28–8.00(2s, 1H),8.88(m, 1H), 7.76(m, 1H), 7.44(m, 2H), 7.23(m, 2H), 6.86(m, 4H), 3.71(m,13H). 217. 3 (DMSO) d 11.64–11.44(2s, 1H), 8.49(m, 516 (M − H)⁻ 2H),7.99(m, 4H), 7.49(m, 4H), 7.18(m, 4H), 6.83(m, 3H), 3.72(m, 5H). 218. 3(DMSO) d 11.67–11.49(2s, 1H), 8.64(m, 620 (M + H)⁺ 1H), 8.49(m, 1H),8.29–8.04(2s, 1H), 7.92(m, 3H), 7.48(m, 4H), 7.16(m, 2H), 6.81(m, 3H),3.70(m, 5H). 219. 3 10.41(s, 1H), 8.00(m, 4H), 7.32(m, 9H), 477 (M + H)⁺3.81(s, 2H), 1.99(s, 3H). 220. 3 10.39(s, 1H), 7.99(m, 4H), 7.51(m, 2H),525 (M + H)⁺ 7.25(m, 2H), 6.83(m, 3H), 3.75(s, 2H), 3.70(s, 3H), 1.94(s,3H). 221. 3 1.40(s, 1H), 7.99(m, 4H), 7.47(m, 5H), 507 (M + H)⁺ 6.83(m,3H), 3.72(s, 2H), 3.69(s, 3H), 1.98(s, 3H). 222. 3 10.46(s, 1H), 8.00(m,4H), 7.35(m, 5H), 525 (M + H)⁺ 6.87(m, 2H), 3.75(s, 2H), 3.70(s, 3H),1.96(s, 3H). 223. 3 10.53(s, 1H), 8.02(m, 4H), 7.46(m, 5H), 545 M+7.25(m, 2H), 3.86(s, 2H), 2.00(s, 3H). 224. 3 (DMSO) d 11.62–11.41(2s,1H), 7.95(m, 509 (M − H)⁻ 4H), 7.43(m, 4H), 7.17(m, 2H), 6.85(m, 3H),3.70(m, 8H), 2.75(m, 4H). 225. 3 (DMSO) d 11.65–11.41(2s, 1H),8.22–7.97(2s, 570 (M − H)⁻ 1H), 7.82(m, 4H), 7.41(m, 2H), 7.16(m, 4H),6.86(m, 3H), 5.40–5.29(2s, 2H), 3.70(m, 5H). 226. 3 (DMSO) d11.66–11.46(2s, 1H), 8.03(m, 577 (M − H)⁻ 3H), 7.52(m, 3H), 7.22(m, 3H),6.80(m, 3H), 3.97(s, 3H), 3.63(m, 5H). 227. 3 (MeOD-d6) 8.83(dd, 1H),8.73(m, 1H), 498 (M + H)+ 8.48–8.20(m, 6H), 7.30(m, 4H), 4.05(S, 1H),3.69(S, 1H) 228. 3 (MeOD-d6) 8.51(dd, 1H), 8.34(d, 1H), 444 (M + H)+7.80(dd, 1H), 7.69(m, 2H), 7.30(m, 5H), 4.03(S, 1H), 3.66(S, 1H),2.33(S, 3H) 229. 3 440 (M + H)+ 230. 3 494 (M + H)+ 231. 4 (DMSO) d11.53–11.32(2s, 1H), 8.22–8.14(2s, 439 (M − H)⁻ 1H), 7.80(m, 1H),7.57(m, 2H), 7.30(m, 9H), 4.94–4.80(2s, 2H), 3.98–3.60(2s, 2H),2.36–2.32(2s, 3H). 232. 4 (DMSO) d 11.50–11.25(2s, 1H), 8.22–8.13(2s,405 (M − H)⁻ 1H), 7.79(m, 1H), 7.56(m, 2H), 7.31(m, 10H), 4.93–4.80(2s,2H), 3.95–3.57(2s, 2H), 2.36–2.31(2s, 3H). 233. 4 (DMSO) d11.48–11.25(2s, 1H), 8.21–8.12(2s, 435 (M − H)⁻ 1H), 7.70(m, 1H),7.55(m, 2H), 7.31(m, 6H), 6.87(m, 3H), 4.94–4.79(2s, 2H), 3.72(m, 5H),2.35–2.31(2s, 3H). 234. 5a (DMSO) 11.70–11.55(m, 1H), 8.51–8.33(m, 345.3(M + H)+ 1H), 8.00–7.92(m, 1H), 7.42–7.19(m, 9H), 6.91–6.85(m, 3H),3.98–3.43(m, 2H), 2.29(s, 3H) 235. 5b (DMSO-d₆) d 11.65, 11.39(s, 1H),359.1766 (M + H)+ 8.54, 8.43(s, 1H), 7.89–7.87(m, 1H), 7.40–7.17(m,12H), 7.05–6.98(m, 1H), 5.15.14–5.11(m, 2H), 3.97, 3.51(s, 2H),2.33–2.31(m, 3H). 236. 5b (DMSO-d₆) d 11.62, 11.38(s, 1H), 389.2 (M +H)+ 8.53, 8.42(s, 1H), 7.90–7.80(m, 1H), 7.40–7.36(m, 3H), 7.22–7.17(m,4H); 7.04–6.98(m, 1H), 6.88–6.78(m, 3H), 5.15–5.12(m, 2H), 3.94, 3.47(s,2H), 3.74, 3.70(s, 3H), 2.33–2.31(m, 3H). 237. 5b (DMSO-d₆)11.80–11.65(m, 1H), 8.54–8.43(m, 402.2 (M + H)+ 3H), 7.90–7.66(m, 2H),7.44–7.23(m, 6H), 7.21–7.19(m, 1H), 7.05–6.89(m, 1H), 5.14–5.13(m, 2H),4.02(s, 1H), 3.34(s, 1H), 1.30–1.28(m, 9H) 238. 5b (DMSO-d₆)11.60–11.55(m, 1H), 8.43–8.38(m, 395.2 (M + H)+ 1H), 8.11–7.74(m, 4H),7.60–7.56(m, 2H), 7.44–7.42(m, 2H), 7.31–7.21(m, 4H), 7.05–7.04(m, 1H),5.65–5.63(m, 2H), 3.96(s, 1H), 3.54(s, 1H), 3.34(s, 3H) 239. 5c(DMSO-d₆) 12.00–11.85(m, 1H), 8.95–8.80(m, 423 (M + H)+ 1H),8.16–8.10(m, 1H), 7.99–7.81(2H), 7.72–7.65(m, 2H), 7.42–7.37(m, 2H),7.27–7.16(m, 1H), 6.93–6.76(m, 4H), 3.92–3.36(m, 5H), 2.35(s, 3H) 240.6a (DMSO-d₆) 12.23(s, 1H), 8.11–8.08(m, 530.0335 M+ 0.5H), 8.04–8.01(m,2H), 7.85–7.80(m, 2H), 7.75(m, 0.5H), 7.62–7.56(m, 2H), 7.54–7.53(m,1H), 7.51–7.46(m, 1H), 7.44–7.37(m, 1H), 7.34–7.27(m, 1H), 6.75–6.68(m,1H), 3.20–3.18(m, 3H) 241. 6a (CDCl₃)(mixture of geometric isomers) d538.0/ (M − H)− 3.73&4.17(2s, 2H); 7.1–7.7(m); 540.0 7.67&7.75(2m, 2H);7.88(s) 7.96&8.06(2m, 2H); 9.5(bs); 10.80(bs). 242. 6a (CDCl₃)(mixtureof geometric isomers) d 494.02 (M − H)− 3.73&4.17(2s, 2H); 7.16(m);7.36(m); 7.47(s); 7.60m; 7.66(m); 7.75(m); 7.89(s); 7.96(m); 8.06(m);9.62(bs); 10.80(bs). 243. 6b (CDCl₃)(mixture of geometric isomers) d474.09 (M − H)− 3.21&3.24(2s, 3H); 4.16(bd, 2H); 6.49&6.58(2d, 1H);7.38(m, 6H); 7.82(m, 4H); 8.17&8.29(2d, 1H); 8.27&8.48(2s, 1H);8.93&8.98(2bs, 1H). 244. 6b (CD₃OD)(mixture of geometric isomers) d508.08 (M − H)− 3.27&3.28(2s, 3H); 3.66&4.11(s&b, 2H); 6.64&6.70(2d,1H); 7.35(m, 6H); 7.84(m, 2H); 7.93(m, 2H); 8.12&8.27(2m, 1H);8.39&8.66(2s, 1H). 245. 6b (CD₃OD)(mixture of geometric isomers) d552.05/ (M − H)− 3.15&3.16(2s, 3H); 3.54&3.98(s&b, 2H); 5546.52&6.59(2d, 1H); 7.21(m, 5H); 7.47(m, 1H); 7.73(m, 2H); 7.81(m, 2H);8.00&8.15(2m, 1H); 8.26&8.54(2s, 1H). 246. 6b (CDCl₃)(mixture ofgeometric isomers) d 534.2 (M − H)− 3.25(s); 3.90(2s); 4.10(m); 6.58(m);6.87(m); 6.96(m); 7.45(m); 7.82(m); 8.20(m); 8.29(m); 8.90&8.96(2bs).247. 6b (CDCl₃) d 3.25(s, 3H); 4.17(m, 2H); 475.13 (M − H)− 6.55(d, 1H);7.33(m); 7.47(m, 1H); 7.83(m, 6H); 8.17(m, 1H); 8.34(s, 1H); 8.56(b);8.67(b); 9.18(s, 1H). 248. 6b (CDCl₃)(mixture of geometric isomers) d517.98 (M − H)− 3.20&3.23(2s, 3H); 3.63&4.05(s + m, 2H); 5.95&6.01(2s,2H); 6.46&6.57(2d, 1H) 6.84(m, 3H); 7.30(m); 7.44(m); 7.80(m, 4H);8.15&8.28(2m, 1H); 8.25&8.50(2s, 1H). 249. 6c (CDCl₃)(mixture ofgeometric isomers) d 463.96 (M − H)− 3.16&3.18(2s, 3H); 3.77(b, 1H);4.18(b, 1H); 6.49(m, 1H); 7.18(m); 7.30(m); 7.77(m, 4H); 8.05(m, 2H);8.50&8.63(2b, 1H). 250. 7 (DMSO-d₆) 11.56(s, 1H), 8.14–8.12(m, 533.0229(M + H)+ 2H), 8.09–8.06(m, 2H), 7.96(s, 1H), 7.91–7.89(m, 1H),7.52–7.48(m, 1H), 7.46–7.37(m, 4H), 7.28–7.25(m, 1H), 7.13–7.11(m 1H),4.63(s, 2H) 251. 7 (DMSO-d₆) 11.51(s, 1H), 8.14–8.12(m, 499.0609 (M +H)+ 2H), 8.09–8.07(m, 2H), 7.97(s, 1H), 7.93–7.90(m, 1H), 7.52–7.43(m,2H), 7.38–7.30(m, 5H), 7.13–7.10(m, 1H), 4.55(s, 2H) 252. 7 (DMSO-d₆)11.55(s, 1H), 8.12–8.10(m, 567.0488 (M + H)+ 2H), 8.08–8.06(m, 2H),7.95(s, 1H), 7.86–7.83(m, 1H), 7.74–7.72(m, 2H), 7.55–7.53(m, 2H),7.52–7.47(m, 1H), 7.44–7.40(m, 1H), 7.13–7.10(m, 1H), 4.72(s, 2H) 253. 8(CDCl₃) d 1.15(m, 1H); 1.25(m, 1H); 519.9 (M + H)+ 2.07(m, 1H); 2.80(m,1H); 3.50(s, 2H); 5.97(m, 3H); 6.78(m, 4H); 7.05(m, 1H); 7.13(m, 1H);7.21(m, 1H); 7.85(m, 2H); 8.02(m, 2H). 254. 9 (MeOD-d6) 8.54(d, 1H),8.01(d, 2H), 452 (M + H)+ 7.82(m, 4H), 7.42(d, 1H), 7.34(t, 1H), 7.26(m,4H), 7.05(t, 1H), 4.41(s, 2H) 255. 10 (DMSO-d₆) 11.76(s, 1H),8.10–8.08(m, 485.0467 (M + H)+ 2H), 8.05–8.03(m, 2H), 7.90(S, 1H),7.87–7.85(m, 2H), 7.72–7.59(m, 4H), 7.47–7.43(m, 1H), 7.40–7.36(m, 1H),7.10–7.07(m, 1H) 256. 10 (DMSO-d₆) 12.15(s, 1H), 8.78–8.76(m, 534.9 (M +H) 1H), 8.29–8.25(m, 2H), 8.11–8.09(m, 1H), 8.06–8.04(m, 2H),7.99–7.97(m, 2H), 7.93(s, 1H), 7.81–7.77(m, 1H), 7.72–7.66(m, 2H),7.59–7.57(m, 1H), 7.42–7.38(m, 1H), 7.35–7.31(m, 1H), 7.04–7.01(m, 1H)

Example 11 Evaluation of Polymerase Activity

Compounds of the present invention can be evaluated for inhibition ofHCV NS5b RNA dependent RNA polymerase activity in assays comprised of asuitable buffer (e.g. 20 mM Tris-HCl pH 7.6), primed or unprimed RNAtemplates, GTP, ATP, CTP, and UTP, MnCl₂ or MgCl₂, and reducing agentsuch as 10 mM dithiothreitol or 2-mercaptoethanol. The assay buffer maycontain salts such as ammonium acetate, KCl, or NaCl, and nonionic orzwitterionic detergents such as Tween or CHAPS. The incorporation ofnucleotides into the complementary RNA strand may be monitored by theincorporation of radiolabeled NTP (e.g. ³H labeled GTP). Suitable RNAtemplates for de novo initiation in the presence of 20–50 μM GTP or ATPare the homopolymers poly rC and poly rU, respectively. HeteropolymerRNA templates with 1–3 cytidine (C) bases or 1–3 uridine (U) bases atthe 3′ terminus of the template may also be used for de novo initiation.Primed RNA templates such as poly rC primed with oligo rG or oligo dG,and poly rA primed with oligo rU may also be used to detect polymeraseactivity. The primers may be any length greater than 10 bases. A biotinresidue may be added to the 5′ end of the template or the 5′ end of theprimer to capture the template and the newly synthesized, complementarystrand on avidin coated spheres. One embodiment of this technologyconsists of a mixture of NS5b polymerase, a poly rC RNA template primedwith 5′ biotinylated oligo rG, 20 mM Tris HCl pH 7.6, 100 mM ammoniumacetate, 10 mM dithiothreitol, 2 mM CHAPS, 1 mM MgCl₂, and 150–200 nM ³Hlabeled GTP. Test compounds (inhibitors) may be incorporated in thereaction mixture with up to 10% DMSO. The reaction is run for varioustimes (1–180 minutes) at 22–37° C., and stopped by the addition of10–140 mM EDTA. Scintillation Proximity Assay avidin-coated beads(Amersham Pharmacia Biotech) are added to capture the ds RNA product; orthe reaction mixtures may be transferred to avidin coated Flash Plates(Perkin Elmer Life Sciences). The incorporation of radiolabeled GTP intothe complementary strand is measured in 96, 384, or 1536 well plates inscintillation counters such as the Wallac Microbeta and PackardTopCount.

Compounds were evaluated for inhibition of viral replication accordingto published procedures (Bartenschlager, R., et. al., Science, 1999,285, 110) with modifications as follows.

HuH-7 replicon cells 5–15 and 9–13 were cultured in Dulbecco's minimalessential medium (DMEM) containing high glucose and supplemented with10% fetal bovine serum (FBS), L-glutamine (2 mM), non-essential aminoacids (1×), Penicillin (100 IU/mL)/Streptomycin (100 μg/mL) and G418(Geneticin, 750 μg/mL). Unless otherwise specified, all media componentswere obtained from Invitrogen. Replicon cell line stocks were maintainedas sub-confluent monolayers by passaging every Monday (1:6 split) andThursday (1:10 split) and incubated at 37° C. with 5% CO₂. Tissueculture plates (96-well white clear bottom plates, Corning #3610) wereseeded at 7×10³ cells/well and incubated for 24 hours prior to additionof the compounds.

Compounds in dry powder form were diluted in DMSO (30 mM stock). Serialdilutions of each Compound in DMSO (10 mM–0.1 mM) were performed in a96-well polypropylene plate using a microtiter format. Culture media(200 μl) was added to the corresponding wells of a sterile 96-well roundbottom plate. Diluted compound (2 μl) was added to the correspondingwells of the medial plate (final compound concentrations: 100 μM–1 μM).Culture media was removed from the corresponding wells of the 96-wellplate containing the replicon cells and 150 μl diluted compound added.Media containing 1% DMSO and a serially diluted IFN were included oneach plate. The cultures were incubated at 37° C. with 5% CO₂ for 3days. Cultures were observed visually for cytotoxicity or compoundprecipitation prior to RNA extraction described below.

Total cellular RNA was extracted by spin column technology (RNeasy 96,Qiagen) using the vacuum methodology according to the manufacturer'sprotocol. In brief, culture media was removed and 100 μl RLT lysisbuffer containing 0.14M β-mercaptoethanol (β-ME) was added to each well.The plate was kept flat on the laboratory bench and shaken vigorously tolyse the cells. An equal volume of 70% ETOH was mixed with the lysateand added to the corresponding columns of the RNeasy 96-well plate.Vacuum was applied to draw the lysate through the filters. Afterventilating the plate, buffer RW1 (1 mL) was drawn through each column.The waste tray was emptied and the filters washed twice with buffer RPE(1 mL/wash). After ventilating the tray, the RNeasy plate was removedand the bottom of the plate struck several times on a stack of papertowels to remove excess wash buffer. The waste tray was removed from thevacuum apparatus and the RNeasy 96-well plate dried by applying vacuumfor 10 minutes. Total cellular RNA was eluted from the columns with twowashes of 60 μl RNase-free water.

Relative quantitative multiplex RT-PCR was performed using TaqMan (TM)EZ RT Core Reagent kit (Perkin Elmer) according to the manufacturer'sprotocol (PE Applied Biosystems User Bulletin #2). Primer 061 (NT 61–82)and 139 (NT 139–158) amplifying a short region in the 5′ untranslatedregion of the HCV genome were utilized at 300 nM final concentrations.Probe #3 (NT 97–119) labeled with FAM reporter dye was utilized at 200nM final concentration. Pre-developed human GAPDH primers and probelabeled with VIC reporter dye were obtained from PE Applied Biosystems(# 4310884E) and used according to the manufacturer's protocol. TMRT-PCR master mix was prepared containing the above primers/probe forboth target RNA. Total cellular RNA (2 μl) was added to the reactiontubes of a 96-well optical plate that corresponded to the wells of thereplicon culture plate. The final volume of each reaction was 50 μl. Astandard curve was prepared from ten-fold serial dilutions of totalcellular RNA extracated from 10⁶ replicon cells and eluted in 30 μlRNase-free water. Thermocycler (7700, Perkin Elmer) conditions consistedof: 50° C. hold for 2 minutes, 70° C. hold for 10 minutes, 60° C. holdfor 30 minutes, 95° C. hold for 5 minutes followed by 40 cycles at 95°C. for 20 seconds and 60° C. for 1 minute. The Thermocycler wasprogrammed for multiplex RT-PCR and cycle threshold values for eachsample converted to μg HCV and GAPDH RNA based on the standard curveusing the Excel computer program. For all samples, the ratio of HCV RNAto GAPDH RNA was calculated. For samples treated with compounds, theratio was compared to untreated cells and reported as percent control.

Table 3 lists inhibitory activity for compounds of the invention. In theTable, activity is indicated as +++ for compounds inhibiting 50% ofreplication at less than 5 uM; ++ for compounds showing inhibitionbetween 5 uM and 50 uM; and + for compounds having inhibitory activitygreater than 50 uM.

TABLE 3 Compound No. IC50 (uM) 1 ++ 2 +++ 3 +++ 4 +++ 5 +++ 6 +++ 7 +++8 +++ 9 +++ 10 +++ 11 +++ 12 + 13 +++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++19 ++ 20 +++ 21 +++ 22 + 23 +++ 24 +++ 25 +++ 26 +++ 27 +++ 28 +++ 29+++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 ++ 37 +++ 38 +++ 39 +++40 +++ 41 +++ 42 +++ 43 +++ 44 +++ 45 +++ 46 ++ 47 ++ 48 +++ 49 ++ 50+++ 51 +++ 52 +++ 53 +++ 54 +++ 55 + 56 +++ 57 +++ 58 + 59 +++ 60 +++ 61+++ 62 +++ 63 +++ 64 +++ 65 ++ 66 ++ 67 ++ 68 +++ 69 + 70 +++ 71 +++ 72+++ 73 +++ 74 +++ 75 +++ 76 ++ 77 +++ 78 ++ 79 ++ 80 +++ 81 + 82 ++ 83+++ 84 +++ 85 + 86 + 87 + 88 +++ 89 ++ 90 ++ 91 + 92 ++ 93 + 94 + 95 +++96 + 97 + 98 ++ 99 +++ 100 +++ 101 ++ 102 +++ 103 +++ 104 +++ 105 ++ 106+++ 107 + 108 + 109 + 110 + 111 + 112 + 113 + 114 + 115 ++ 116 + 117 +++118 ++ 119 +++ 120 ++ 121 +++ 122 ++ 123 +++ 124 +++ 125 +++ 126 ++ 127++ 128 +++ 129 ++ 130 + 131 +++ 132 + 133 + 134 +++ 135 +++ 136 + 137 ++138 + 139 + 140 + 141 + 142 +++ 143 ++ 144 + 145 +++ 146 +++ 147 +++ 148+++ 149 +++ 150 +++ 151 +++ 152 +++ 153 +++ 154 +++ 155 +++ 156 +++ 157+++ 158 +++ 159 ++ 160 ++ 161 ++ 162 ++ 163 +++ 164 +++ 165 +++ 166 +++167 +++ 168 +++ 169 +++ 170 +++ 171 +++ 172 +++ 173 +++ 174 +++ 175 +++176 +++ 177 +++ 178 +++ 179 + 180 +++ 181 ++ 182 +++ 183 +++ 184 +++ 185+++ 186 +++ 187 +++ 188 +++ 189 + 190 +++ 191 + 192 +++ 193 +++ 194 +++195 +++ 196 +++ 197 +++ 198 +++ 199 +++ 200 +++ 201 +++ 202 + 203 +++204 +++ 205 ++ 206 +++ 207 +++ 208 ++ 209 +++ 210 ++ 211 ++ 212 +++ 213++ 214 ++ 215 + 216 ++ 217 ++ 218 + 219 + 220 + 221 + 222 + 223 + 224 +225 + 226 +++ 227 +++ 228 +++ 229 +++ 230 +++ 231 +++ 232 +++ 233 +++234 + 235 + 236 + 237 + 238 ++ 239 ++ 240 1 241 + 242 + 243 +++ 244 +++245 +++ 246 +++ 247 +++ 248 +++ 249 +++ 250 ++ 251 ++ 252 ++ 253 + 254 +255 ++ 256 ++

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit or scope of the appended claims.

1. A compound of formula (Ib),

wherein: A is selected from the group consisting of —OSO₂-M, —NR₂SO2-M,—OCR₂R′₂-M and —CR₂R′₂SO_(n)-M; R₁ is selected from the group consistingof C₁₋₆ alkyl, halogen, —CN, C₁₋₆-alkoxy, C₁₋₆-fluoroalkyl,C₁₋₆-fluroalkoxy and C₁₋₆-alkylthio; R₂ and R′₂ are independentlyselected from the group consisting of H and C₁₋₆ alkyl; M and M′ areindependently selected from aryl optionally substituted with 1 to 3 R₁,heteroaryl optionally substituted with 1 to 3 R₁ and cycloalkyl of 3 to8 carbons; and n=0, 1, or 2; or a pharmaceutically acceptable saltthereof.
 2. A compound of formula (Ic),

wherein: R₁ is selected from the group consisting of C₁₋₆ alkyl,halogen, —CN, C₁₋₆-alkoxy, C₁₋₆-fluoroalkyl, C₁₋₆-fluroalkoxy andC₁₋₆-alkylthio; and M and M′ are independently selected from aryloptionally substituted with 1 to 3 R₁, heteroaryl optionally substitutedwith 1 to 3 R₁ and cycloalkyl of 3 to 8 carbons; or a pharmaceuticallyacceptable salt or prodrug thereof.
 3. A compound according to claim 2,wherein M and M′ are aryl optionally substituted with 1 to 3 R, or apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 2, wherein M and M′ are heteroaryl optionally substituted with 1to 3 R₁, or a pharmaceutically acceptable salt thereof.
 5. A compoundselected from the group consisting of:N-(2-{(E)-[(2,5-dichlorobenzoyl)hydrazono]methyl}phenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide;2-((E)-{2-[2-(1,3-benzodioxol-5-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;2-((E)-{2-[(4-methylphenyl)sulfonyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;3-chloro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;N-[2-((E)-{[(3-bromophenyl)acetyl]hydrazono}methyl)phenyl]-N-methyl-4-(trifluoromethyl)benzenesulfonamide;2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)phenyl4-methylbenzenesulfonate;2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-3-methylphenyl4-(trifluoromethyl)benzenesulfonate;2-((E)-{2-[2-fluoro-6-(trifluoromethyl)benzoyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;2-((E)-{2-[2-(trifluoromethyl)benzoyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;N-(2-{(E)-[(1,3-benzodioxol-5-ylacetyl)hydrazono]methyl}phenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide;2-{(E)-[2-(2-bicyclo[2.2.1]hept-2-ylacetyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;N-methyl-N-(2-{(E)-[(phenylacetyl)hydrazono]methyl}phenyl)-4-(trifluoromethyl)benzenesulfonamide;N-[2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)phenyl]-N-methyl-4-(trifluoromethyl)benzenesulfonamide;2-{(E)-[2-(2,6-difluorobenzoyl)hydrazono]methyl}phenyl-4-(trifluoromethyl)benzenesulfonate;2-((E)-{2-[2-(6-chloropyridin-3-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;2-((E)-{2-[2-(3-chlorophenyl)acetyl]hydrazono}methyl)phenyl-4-(trifluoromethyl)benzenesulfonate;2-{(E)-[2-(2-thien-2-ylacetyl)hydrazono]methyl}phenyl-4-(trifluoromethyl)benzenesulfonate;4-fluoro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)phenyl-4-(trifluoromethyl)benzenesulfonate;3-chloro-2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)phenyl-4-(trifluoromethyl)benzenesulfonate;4-fluoro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)phenyl-4-methylbenzenesulfonateand2-(3-methoxyphenyl)-N′-[(1E)-(2-{[(4-methylphenyl)sulfonyl]methyl}phenyl)methylene]acetohydrazide;or a pharmaceutically acceptable salt thereof.
 6. A method for treatinga hepatitis C viral infection comprising administering, to an animal inneed thereof, an effective amount of a compound according to claim
 1. 7.A method according to claim 6, wherein the compound is selected from thegroup consisting of:N-(2-{(E)-[(2,5-dichlorobenzoyl)hydrazono]methyl}phenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide;2-((E)-{2-[2-(1,3-benzodioxol-5-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;2-((E)-{2-[(4-methylphenyl)sulfonyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;3-chloro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;N-[2-((E)-{[(3-bromophenyl)acetyl]hydrazono}methyl)phenyl]-N-methyl-4-(trifluoromethyl)benzenesulfonamide;2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;2-((E)-{2-[2-(3-methoxyphenyl)acetyl]hydrazono}methyl)phenyl4-methylbenzenesulfonate;2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)-3-methylphenyl4-(trifluoromethyl)benzenesulfonate;2-((E)-{2-[2-fluoro-6-(trifluoromethyl)benzoyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;2-((E)-{2-[2-(trifluoromethyl)benzoyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;N-(2-{(E)-[(1,3-benzodioxol-5-ylacetyl)hydrazono]methyl}phenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide;2-{(E)-[2-(2-bicyclo[2.2.1]hept-2-ylacetyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;N-methyl-N-(2-{(E)-[(phenylacetyl)hydrazono]methyl}phenyl)-4-(trifluoromethyl)benzenesulfonamide;N-[2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)phenyl]-N-methyl-4-(trifluoromethyl)benzenesulfonamide;2-{(E)-[2-(2,6-difluorobenzoyl)hydrazono]methyl}phenyl4-(trifluoromethyl)benzenesulfonate;2-((E)-{2-[2-(6-chloropyridin-3-yl)acetyl]hydrazono}methyl)phenyl4-(trifluoromethyl)benzenesulfonate;2-((E)-{2-[2-(3-chlorophenyl)acetyl]hydrazono}methyl)phenyl-4-(trifluoromethyl)benzenesulfonate;2-{(E)-[2-(2-thien-2-ylacetyl)hydrazono]methyl}phenyl-4-(trifluoromethyl)benzenesulfonate;118 or4-fluoro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)phenyl-4-(trifluoromethyl)benzenesulfonate;3-chloro-2-((E)-{[(3-chlorophenyl)acetyl]hydrazono}methyl)phenyl-4-(trifluoromethyl)benzenesulfonate;4-fluoro-2-((E)-{[(3-methoxyphenyl)acetyl]hydrazono}methyl)phenyl-4-methylbenzenesulfonate;and2-(3-methoxyphenyl)-N′-[(1E)-(2-{[(4-methylphenyl)sulfonyl]methyl}phenyl)methylene]acetohydrazide;or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically or prophylactically effective amount of a compoundaccording to claim 1.